Indene derivatives useful in treating pain and inflammation

ABSTRACT

Compounds of formula (1): wherein, R 1 , R 2 , R 3 , R 4a , R 4b  and R 5  are described herein, or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, are described herein, as well as other compounds. These compounds are useful in treating inflammation and/or pain. Compositions comprising a compound of the invention are also disclosed, as are methods of using the compounds to treat inflammation and/or pain.

CROSS REFERENCE TO PRIOR APPLICATION

This application is a continuation of U.S. patent application Ser. No.17/045,675 (filed on Oct. 6, 2020), which is a National Stage PatentApplication of PCT International Patent Application No.PCT/US2019/026138 (filed on Apr. 5, 2019) under 35 U.S.C. § 371, whichclaims priority to U.S. Provisional Patent Application No. 62/654,191(filed on Apr. 6, 2018), which are all hereby incorporated by referencein their entirety.

FIELD OF THE INVENTION

The present invention is generally directed to indene derivatives whichare useful in treating inflammation and/or pain, as well as tocompositions and methods related to the same.

BACKGROUND OF THE INVENTION

Tissue injury results in the initiation of a complex cascade of cellularevents which result in redness, swelling, heat and pain at the site ofinsult. This inflammatory response is the normal mechanism by which thebody contains and removes pathogens and repairs tissue damage. Theseclassic and acute signs of inflammation are in large part attributableto the influx and accumulation of activated leukocytes and thesubsequent release of mediators such as histamine, leukotrienes,substance P, prostaglandins, cytokines, reactive oxygen species andproteases. Activated immune cells and their proinflammatory products canalso induce sensitization of peripheral nociceptors, contributing to thedevelopment of both acute and chronic inflammatory pain.

Normal inflammation is a tightly controlled, temporary, process,involving many different cell types, and is ultimately followed by aresolution phase featuring the expression of anti-inflammatory mediatorsand involving cell subsets that coordinate the tissue repair process.Inflammatory disease occurs when this normal cycle of activation/repairgoes awry, resulting in a chronic state of immune cell activation andmisdirection of the immune response towards host tissue. Inflammatorypain is also a protective response, designed to shield the injuredtissue from further damage, but under conditions of uncontrolledinflammation, the multi-faceted interplay between the immune and nervoussystems can drive the establishment of chronic pain and create a host ofpathologies which are difficult to manage, creating a large personal andeconomic burden on society.

One of the key signaling pathways involved in the initiation andpropagation of immune cell activation is the phosphoinositide-3-kinase(PI3K) pathway. In response to extracellular signals, phosphoinositide3-kinase (PI3K) becomes activated and phosphorylatesphosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) within the plasmamembrane to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3).PIP3 then initiates a cascade of downstream signaling pathways byinteracting with pleckstrin homology (PH) domain-containing proteins,such as protein kinase B (PKB, also known as Akt), that regulatecellular activation, function, proliferation and/or survival, dependingon the cell type and stimulus (Deane et al., Annu Rev Immunol 22,563-598, 2004). Cellular levels of PIP3 are normally tightly regulatedby PI3K, the inositol 5-phosphatases SHIP1 (SH2 domain-containinginositol phosphatase), SHIP2, and by the inositol 3-phosphatase PTEN.

To date, a number of small molecule SHIP1 modulators have beendisclosed, including sesquiterpene compounds such as pelorol. Otherreported SHIP1 modulators include the compounds described in U.S. Pat.Nos. 8,765,994, 7,601,874, 9,000,050, 9,540,353, and 9,765,085 U.S.Published Patent Application No. 2017/0253596.

Pain is another critical component of a body's defense system. Ingeneral, pain is a basic bodily sensation induced by a noxious stimulus,received by nerve endings (nociceptive receptors) and characterized byphysical discomfort (such as pricking, throbbing, or aching), andtypically leads to evasive action (i.e., removing oneself from thesource of the stimulus). Pain is typically classified into two maincategories: acute and chronic pain.

Acute or nociceptive pain is part of a rapid warming relay instructingthe motor neurons of the central nervous system to minimize detectedphysical harm. It is mediated by nociceptors, which are free nerveendings that terminate just below the skin, in tendons, joints, and inbody organs. They serve to detect cutaneous pain, somatic pain andvisceral pain. Nociception can be associated with nerve damage caused bytrauma, diseases such as diabetes, shingles, irritable bowel syndrome,late stage cancer or the toxic effects of chemotherapy.

Chronic pain is typically classified into two types: inflammatorynociceptive pain and neuropathic pain. Inflammatory nociceptive pain isassociated with tissue damage and the resulting inflammatory process.

Neuropathic pain is produced by damage to and/or inflammation of theneurons in the peripheral and central nervous systems and involvessensitization of these systems.

One of the challenges for researchers is that chronic pain may involve amix of both inflammatory and neuropathic components. In inflammatorynociceptive pain, inflammation may cause damage to the neurons andproduce neuropathic pain.

Likewise, neuronal injury may cause an inflammatory reaction (neurogenicinflammation) that contributes to inflammatory pain.

While significant strides have been made in the field ofanti-inflammatory agents and analgesics, there remains a need foreffective small molecule for the treatment of inflammation and/or pain.There is also a need for pharmaceutical compositions containing suchcompounds, as well as for methods relating to the use thereof to treatdiseases, disorders or conditions that would benefit from suchtreatment. The present invention fulfills these needs, and providesother related advantages.

SUMMARY OF THE INVENTION

The present invention is generally directed to compounds which areuseful in treating inflammation and/or pain, pharmaceutical compositionscomprising the compounds and methods of using the compounds and thepharmaceutical compositions of the invention for the treatment ofinflammation and/or pain.

Accordingly, in one aspect, this invention is directed to compounds offormula (I):

wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4b) is —R⁹—OR⁷ and R^(4b) is hydrogen, alkyl or optionally    substituted heteroaryl; or R⁴ is an optionally substituted aryl and    R^(4b) is a bond to C16;-   or R^(4a) and R^(4b) together form alkylidene, provided that

is a fused 5- or 6-membered N-heteroaryl substituted by substitutedaryl, substituted aralkyl, substituted cycloalkyl or substitutedheteroaryl;

-   or R^(4a) is alkyl and R^(4b) is hydrogen, provided that

is a fused 5- or 6-membered N-heteroaryl substituted by substitutedaryl, substituted aralkyl, substituted cycloalkyl or substitutedheteroaryl;

-   or R^(4a) and R¹ together form an optionally substituted bicyclic    heterocyclyl and R^(4c) is hydrogen;-   or R^(4a), R^(4b) and R¹ together form a fused optionally    substituted heteroaryl;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl; and-   R⁹ is a direct bond or a straight or branched alkylene chain;-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, this invention is directed to compositions comprisinga pharmaceutically acceptable excipient, carrier and/or diluent and acompound of formula (I), or a stereoisomer, enantiomer or tautomerthereof or mixtures thereof; or a pharmaceutically acceptable salt orsolvate thereof.

In another aspect, this invention is directed to methods for treatinginflammation and/or pain in a mammal comprising administering aneffective amount of a compound of formula (I), or a stereoisomer,enantiomer or tautomer thereof or mixtures thereof; or apharmaceutically acceptable salt or solvate thereof, as set forth above,to the mammal in need thereof.

In another aspect, this invention is directed to methods for treatinginflammation and/or pain in a mammal comprising administering acomposition comprising an effective amount of a compound of formula (I),or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof;or a pharmaceutically acceptable salt or solvate thereof, as set forthabove, to the mammal in need thereof.

In another aspect, this invention is directed to methods of preparingcompounds of formula (I), or stereoisomers, enantiomers or tautomersthereof or mixtures thereof; or pharmaceutically acceptable salts orsolvates thereof.

In another aspect, this invention is directed to the use of thecompounds of the invention, as set forth above, or a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt or solvate thereof, or the use of apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of the invention, as set forth above, or astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt or solvate thereof, in the preparationof a medicament for the treatment of inflammation and/or pain.

These aspects and embodiments thereof are described in more detailbelow.

To this end, various references are set forth herein which describe inmore detail certain background information, procedures, compounds and/orcompositions, and are each hereby incorporated by reference in theirentirety.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Oxo” refers to ═O.

“Cyano” refers to —CN.

“Nitro” refers to —NO₂.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toten carbon atoms, more preferably one to eight carbon atoms, mostpreferably one to six carbon atoms and which is attached to the rest ofthe molecule by a single bond, e.g., methyl, ethyl, n-propyl,1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl(t-butyl), 3-methylhexyl, 2-methylhexyl, 6-methylheptan-2-yl,5-ethyl-6-methylheptan-2-yl and the like. When specifically stated inthe specification, an alkyl group may be optionally substituted by oneof the following groups: alkyl, halo, haloalkyl, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR²⁰,—OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,—N(R²⁰)C(O)OR²², —N(R²⁰)C(O)R², —N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—S(O)_(p)OR²² (where p is 1 to 2), —S(O)_(t)R²² (where t is 0 to 2), and—S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR²² is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, having from two to twelve carbon atoms,preferably one to eight carbon atoms and which is attached to the restof the molecule by a single bond, e.g., ethenyl, prop-1-enyl,but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Whenspecifically stated in the specification, an alkenyl group may beoptionally substituted by one of the following groups: alkyl, halo,haloalkyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl,oxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR², —N(R²⁰)C(O)R², —N(R²⁰)S(O)_(p)R²² (where pis 1 to 2), —S(O)_(p)OR²² (where p is 1 to 2), —S(O)_(t)R² (where t is 0to 2), and —S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; and each R²² is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, e.g., —CH₂—, —CH₂CH₂—,—CH₂CH₂—CH₂, and the like. The alkylene chain is attached to the rest ofthe molecule through a single bond and to the radical group through asingle bond. The radical group can be attached to any carbon in thealkylene chain. When specifically stated in the specification, analkylene chain may be optionally substituted by one of the followinggroups: alkyl, alkenyl, halo, cyano, nitro, aryl, cycloalkyl,heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰,—N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²²,—N(R²⁰)C(O)R²², —N(R²⁰)S(O)_(p)R² (where p is 1 to 2), —S(O)OR² (where pis 1 to 2), —S(O)_(t)R² (where t is 0 to 2), and —S(O)_(p)N(R²⁰)₂ (wherep is 1 to 2) where each R²⁰ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R² is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylidene” refers to a straight or branched hydrocarbon radical groupconsisting solely of carbon and hydrogen, containing at least one doublebond, having from one to seven carbon atoms, and that is attached to therest of the molecule through a double bond, e.g., methylene, ethylidene,propylidene, and the like. When specifically stated in thespecification, an alkylidene radical may be optionally substituted byone of the following groups: alkyl, halo, haloalkyl, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR²⁰,—OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,—N(R²⁰)C(O)OR²², —N(R²⁰)C(O)R²², —N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—S(O)_(p)OR²² (where p is 1 to 2), —S(O)_(t)R²² (where t is 0 to 2), and—S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR² is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems. Aryl radicals include, but are not limited to, arylradicals derived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. When specificallystated in the specification, an aryl group may be optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, alkenyl, halo, haloalkyl, cyano, nitro, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²²,—R²¹—N(R²⁰)C(O)R²², —R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—R²¹—N═C(OR²⁰)R²⁰, —R²¹—S(O)OR² (where p is 1 to 2), —R²¹—S(O),R² (wheret is 0 to 2), and —R²¹—S(O),N(R²)₂ (where p is 1 to 2) where each R²⁰ isindependently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,cycloalkylalkyl, optionally substituted aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R²¹ isindependently a direct bond or a straight or branched alkylene chain;and each R²² is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. When specifically stated in the specification, the alkylene chainpart of the aralkyl radical may be optionally substituted as describedabove for an optionally substituted alkylene chain. When specificallystated in the specification, the aryl part of the aralkyl radical may beoptionally substituted as described above for an optionally substitutedaryl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptly, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, and the like. When specifically stated in thespecification, a cycloalkyl group may be optionally substituted by oneor more substituents independently selected from the group consisting ofalkyl, halo, haloalkyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰,—R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²²,—R²¹—N(R²⁰)C(O)R²², —R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—R²¹—N═C(OR²⁰)R²⁰, —R²¹—S(O)OR²² (where p is 1 to 2), —R²¹—S(O)_(t)R²²(where t is 0 to 2), and —R²¹—S(O)_(p)N(R²²)₂ (where p is 1 to 2) whereeach R²⁰ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R²¹ is independently a direct bondor a straight or branched alkylene chain; and each R² is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g) whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above. When specifically stated in the specification,the alkylene chain and/or the cycloalkyl radical may be optionallysubstituted as defined above for optionally substituted alkylene chainand optionally substituted cycloalkyl.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which consists of two to twelve carbon atoms and from one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include spiro, fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperdinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene,tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl and 1,6-dioxaspiro[4.5]decanyl. Whenspecifically stated in the specification, a heterocyclyl group may beoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo,nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰,—R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²)C(O)OR²², —R²¹—N(R²⁰)C(O)R²²,—R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2), —R²¹—N═C(OR²)R²⁰,—R²¹—S(O)OR² (where p is 1 to 2), —R²¹—S(O)_(t)R²² (where t is 0 to 2),and —R²¹—S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ isindependently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R²¹ is independently a direct bondor a straight or branched alkylene chain; and each R²² is alkyl,alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere the optional substituents on the heterocyclyl, heterocyclylalkyl,heteroaryl and heteroarylalkyl substitutents are selected from alkyl,halo or haloalkyl.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. When specifically stated in thespecification, the alkylene chain of the heterocyclylalkyl radical maybe optionally substituted as defined above for an optionally substitutedalkylene chain. When specifically stated in the specification, theheterocyclyl part of the heterocyclylalkyl radical may be optionallysubstituted as defined above for an optionally substituted heterocyclylgroup.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocydic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzo[d]imidazolyl, benzimidazopyrimidinyl,benzo[4,5]imidazo[1,2-a]pyrimidinyl, benzthiazolyl, benzindolyl,benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzo[d]isoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl,benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-a]pyrazinyl, imidazo[1,5-a]pyrazinyl, imidazolyl, indolyl,indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl,indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl,1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl,purinyl, pyrrolyl, pyrazolyl, pyrdinyl, pyridinonyl, pyrazinyl,pyrimidinyl, pryrimidinonyl, pyridazinyl,pyrido[2,3-d]pyrimidinonyl,pyrazolo[1,5-a]pyrimidinyl, quinazolinyl,quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl,thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl,tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). When specificallystated in the specification, a heteroaryl group may be optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo,nitro, thioxo, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl,optionally substituted heteroaryl,heteroarylalkyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R², —R²¹—C(O)R²⁰,—R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R¹⁰)C(O)OR²²,—R²¹—N(R²⁰)C(O)R²², —R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—R²¹—N═C(OR²⁰)R²⁰, —R²¹—S(O)_(p)OR²² (where p is 1 to 2),—R²¹—S(O)_(t)R² (where t is 0 to 2), and —R²¹—S(O)_(p)N(R²⁰)₂ (where pis 1 to 2) where each R²⁰ is independently hydrogen, alkyl, alkenyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R²¹ isindependently a direct bond or a straight or branched alkylene chain;and each R²² is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen. The point of attachment of theN-heteroaryl to the rest of the molecule can be through a nitrogen atomor a carbon atom in the N-heteroaryl. When specifically stated in thespecification, an N-heteroaryl radical may be optionally substituted asdescribed above for an optionally substituted heteroaryl radical.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above. When specifically stated in the specification,the heteroaryl part of the heteroarylalkyl radical may be optionallysubstituted as defined above for an optionally substituted heteroarylgroup. When specifically stated in the specification, the alkylene chainpart of the heteroarylalkyl radical may be optionally substituted asdefined above for an optionally substituted alkylene chain.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets, (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution (“unsubstituted”). When a functional group is described as“optionally substituted,” and in turn, substitutents on the functionalgroup are also “optionally substituted” and so on, for the purposes ofthis invention, such iterations are limited to five, preferably suchiterations are limited to two.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent. Furthermore, some of the crystalline forms of thecompounds of the invention may exist as polymorphs, which are includedin the present invention.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, ofinflammation and/or pain in the mammal, preferably a human. The amountof a compound of the invention which constitutes a “therapeuticallyeffective amount” will vary depending on the compound, the inflammationand/or pain and its severity, the manner of administration, and the ageof the mammal to be treated, but can be determined routinely by one ofordinary skill in the art having regard to his own knowledge and to thisdisclosure.

“Treating” or “treatment” as used herein covers the treatment ofinflammation and/or pain in a mammal, preferably a human, having theinflammation and/or pain, and includes:

(a) preventing the inflammation and/or pain from occurring in a mammal,in particular, when such mammal is predisposed to the condition but hasnot yet been diagnosed as having it;

(b) inhibiting the inflammation and/or pain, i.e., arresting itsdevelopment;

(c) relieving (or ameliorating) the inflammation and/or pain, i.e.,causing regression of the inflammation and/or pain; or

(d) relieving (or ameliorating) the symptoms resulting from theinflammation and/or pain, e.g., relieving inflammation and/or painwithout addressing the underlying disease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts or solvates thereof, may contain one or more asymmetric centresand may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.Compounds of the invention may also possess axial chirality which mayresult in atropisomers. The present invention is meant to include allsuch possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallisation. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh-pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes enantiomers,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another. See, for example, Smith, M.B. and J.March, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 6th edition (Wiley, 2007), for a detailed description of thestructure and properties of enantiomers and stereoisomers.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

Certain carbons are identified by numerals in the formulae of thecompounds of the invention. For purposes herein, the carbon at numeral14 in formula (I) is indicated herein as C14 and the carbon at numeral16 is indicated herein as C16, and so forth. These numerals may or maynot be the same as the locants in the compound names given herein.

When a substituent is indicated as being substituted, such as —R⁹—OR⁷,it is understood that the substituent may be substituted by theindicated substituent at any carbon in the substituent. Thus, forexample, when the R⁹ in the —R⁹—OR⁷ substituent is an alkylene chain,the —OR⁷ group in the —R⁹—OR⁷ group can be on any carbon in the R⁹alkylene chain.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using ChemDraw 17.0software program, wherein the compounds of the invention are namedherein as derivatives of a central core structure. For complex chemicalnames employed herein, a substituent group is named before the group towhich it attaches. For example, cyclopropylethyl comprises an ethylbackbone with cyclopropyl substituent. In chemical structure diagrams,all bonds are identified, except for some carbon atoms, which areassumed to be bonded to sufficient hydrogen atoms to complete thevalency.

Thus, for example, a compound of formula (I) wherein

is 1-(4-(4-carboxyphenoxy)phenyl)pyrazolyl, R¹ is hydrogen, R² is—CH₂OH, R³ is —CH₂—NH₂, R^(4a) and R^(4b) together form methylene and R⁵is methyl, i.e., a compound of the following structure:

is named herein as4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenoxy)benzoicacid.

Embodiments of the Invention

Of the various aspects of the invention set forth above in the Summaryof the Invention, certain embodiments are preferred.

Of the compounds of formula (I), or a stereoisomer, enantiomer ortautomer thereof or mixtures thereof, or a pharmaceutically acceptablesalt or solvate thereof, as described above in the Summary of theInvention, a first embodiment are compounds of formula (I) wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) is —R⁹—OR⁷ and R^(4b) is hydrogen, alkyl or optionally    substituted heteroaryl;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R^(e) is independently selected from a direct bond or a    straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl; and-   R⁹ is a direct bond or a straight or branched alkylene chain;-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R₈)₂;-   R⁴ is —R⁶—OR⁷ and R^(4b) is hydrogen, alkyl or optionally    substituted heteroaryl;-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl; and-   R⁹ is a direct bond;-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

One embodiment of this embodiment are compounds of formula (I) wherein:

is a fused 5-membered N-heteroaryl optionally substituted by one or moresubstitutents selected from alkyl, haloalkyl, —C(O)OR⁷, —N(R⁸)₂,—C(O)N(R⁸)₂ or optionally substituted aryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) is —R⁶—OR⁷ and R^(4b) is hydrogen, alkyl or optionally    substituted heteroaryl;-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl; and-   R⁹ is a direct bond;-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   (1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol;-   (1R,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol;-   (1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-1-ol;-   (1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol;-   (1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol;-   (1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol;-   and    (1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyrdin-2-yl)octahydro-1H-inden-1-ol.

Another embodiment of this embodiment are compounds of formula (I)wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂,-   R⁴ is —R⁶—OR⁷ and R^(4b) is hydrogen, alkyl or optionally    substituted heteroaryl;-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl; and-   R⁹ is straight or branched alkylene chain;-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is a fused 5-membered N-heteroaryl optionally substituted by one or moresubstitutents selected from alkyl, haloalkyl, —C(O)OR⁷, —N(R⁸)₂,—C(O)N(R⁸)₂ or optionally substituted aryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) is —R⁹—OR⁷ and R^(4b) is hydrogen, alkyl or optionally    substituted heteroaryl;-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl; and-   R⁹ is a straight or branched alkylene chain;-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment is the compound of formula formula (I)selected from:

-   (2S,5R)-5-ethyl-2-((1R,3aS,4S,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-yl)-6-methylheptan-3-ol.

Of the compounds of formula (I), or a stereoisomer, enantiomer ortautomer thereof or mixtures thereof, or a pharmaceutically acceptablesalt or solvate thereof, as described above in the Summary of theInvention, a second embodiment are compounds of formula (I) wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) and R¹ together form an optionally substituted bicyclic    heterocyclyl and R^(4b) is hydrogen;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl, or a    stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or    a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) and R¹ together form an optionally substituted bicyclic    heterocyclyl and R^(4b) is hydrogen;-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and each    R⁸ is independently selected from hydrogen or alkyl, or a    stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or    a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is a fused 5-membered N-heteroaryl optionally substituted by one or moresubstitutents selected from alkyl, haloalkyl, —C(O)OR⁷, —N(R⁸)₂,—C(O)N(R⁸)₂ or optionally substituted aryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) and R¹ together form an optionally substituted bicyclic    heterocyclyl and R^(4b) is hydrogen;-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and each    R⁸ is independently selected from hydrogen or alkyl, or a    stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or    a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   ((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(hydroxymethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;    and-   ((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(aminomethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.

Of the compounds of formula (I), or a stereoisomer, enantiomer ortautomer thereof or mixtures thereof, or a pharmaceutically acceptablesalt or solvate thereof, as described above in the Summary of theInvention, a third embodiment are compounds of formula (I) wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂, or R^(4a), R^(4b) and R¹ together form    a fused optionally substituted heteroaryl;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl,-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂,-   or R^(4a), R^(4b) and R¹ together form a fused optionally    substituted heteroaryl;-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl, or a    stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or    a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is a fused 5-membered N-heteroaryl optionally substituted by one or moresubstitutents selected from alkyl, haloalkyl, —C(O)OR⁷, —N(R⁸)₂,—C(O)N(R⁸)₂ or optionally substituted aryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁶)₂;-   or R^(4a), R^(4b) and R¹ together form a fused optionally    substituted heteroaryl;-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl,-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   ((4aS,5R,6S,8aS)-6-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-5-yl)methanol;-   ((5R,6S)-5-((4aS,5R,6S,8aS)-5-(aminomethyl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((5aS,6R,7S,9aS)-6-(aminomethyl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridin-7-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;    and-   ((5aS,6R,7S,9aS)-7-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyrdin-6-yl)methanol.

Of the compounds of formula (I), or a stereoisomer, enantiomer ortautomer thereof or mixtures thereof, or a pharmaceutically acceptablesalt or solvate thereof, as described above in the Summary of theInvention, a fourth embodiment are compounds of formula (I) wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) is an optionally substituted aryl and R^(4b) is a bond to    C16.-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl, or a    stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or    a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R⁴ is an optionally substituted aryl and R^(4b) is a bond to C16.-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl,-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is a fused 5-membered N-heteroaryl optionally substituted by one or moresubstitutents selected from alkyl, haloalkyl, —C(O)OR⁷, —N(R⁸)₂,—C(O)N(R⁸)₂ or optionally substituted aryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) is an optionally substituted aryl and R^(4b) is a bond to    C16.-   R⁵ is alkyl;-   each R⁶ is a straight or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl,-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   ((5R,6S)-5-((3aS,6S,7R,7aS)-7-(aminomethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;    and-   ((5R,6S)-5-((3aS,6S,7R,7aS)-7-(hydroxymethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.

Of the compounds of formula (I), or a stereoisomer, enantiomer ortautomer thereof or mixtures thereof, or a pharmaceutically acceptablesalt or solvate thereof, as described above in the Summary of theInvention, a fifth embodiment are compounds of formula (I) wherein:

is a fused 5- or 6-membered N-heteroaryl substituted by substitutedaryl, substituted aralkyl, substituted cycloalkyl or substitutedheteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂,-   R^(4a) and R^(4b) together form alkylidene;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁵ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl;-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is a fused pyrazolyl substituted by substituted aryl, substitutedaralkyl, substituted cycloalkyl or substituted heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) and R^(4b) together form alkylidene;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl.

Of this embodiment, a first embodiment are compounds of formula (I)wherein:

is a fused pyrazolyl substituted by aryl substituted by one or moresubstituents selected from halo, —R¹⁰—OR¹¹, —R¹⁰—C(O)R¹¹ or—R¹⁰—C(O)OR¹¹;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) and R^(4b) together form alkylidene;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl;-   each R¹⁰ is independently a direct bond or a straight or branched    alkylene chain; and-   each R¹¹ is independently hydrogen, alkyl, cycloalkyl or optionally    substituted aryl.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenoxy)benzoic    acid;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   (4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-1-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   (4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenoxy)benzoic    acid;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   (4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone;-   (4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone;-   4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzoic    acid; and-   4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzoic    acid.

Of this embodiment, a second embodiment are compounds of formula (I)wherein:

is a fused pyrazolyl substituted by aralkyl substituted by one or moresubstituents selected from halo, —R¹⁰—OR¹¹ or —R¹⁰—C(O)R¹¹;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) and R^(4b) together form alkylidene;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl;-   R¹⁰ is a direct bond or a straight or branched alkylene chain; and-   each R¹⁰ is independently a direct bond or a straight or branched    alkylene chain; and-   each R¹¹ is independently hydrogen, alkyl, cycloalkyl or optionally    substituted aryl.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;    and-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.

Of this embodiment, a third embodiment are compounds of formula (I)wherein:

is a fused pyrazolyl substituted by cycloalkyl substituted by one ormore substituents selected from halo, —R¹⁰—OR¹¹ or —R¹⁰—C(O)R¹¹;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) and R^(4b) together form alkylidene;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R^(a) is independently selected from hydrogen or alkyl;-   each R¹⁰ is independently a direct bond or a straight or branched    alkylene chain; and-   each R¹¹ is independently hydrogen, alkyl, cycloalkyl or optionally    substituted aryl.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;    and-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.

Of this embodiment, a fourth embodiment are compounds of formula (I)wherein:

is a fused pyrazolyl substituted by heteroaryl substituted by one ormore substituents selected from halo, —R¹⁰—OR¹¹ or —R¹⁰—C(O)R¹¹;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂,-   R^(4a) and R^(4b) together form alkylidene;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl;-   each R¹⁰ is independently a direct bond or a straight or branched    alkylene chain; and each R¹¹ is independently hydrogen, alkyl,    cycloalkyl or optionally substituted aryl.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;    and-   ((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol.

Of the compounds of formula (I), or a stereoisomer, enantiomer ortautomer thereof or mixtures thereof, or a pharmaceutically acceptablesalt or solvate thereof, as described above in the Summary of theInvention, a sixth embodiment are compounds of formula (I) wherein:

is a fused 5- or 6-membered N-heteroaryl substituted by substitutedaryl, substituted aralkyl, substituted cycloalkyl or substitutedheteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) is alkyl and R^(4b) is hydrogen;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl;-   or a stereoisomer, enantiomer or tautomer thereof or mixtures    thereof, or a pharmaceutically acceptable salt or solvate thereof.

Of this embodiment, an embodiment are compounds of formula (I) wherein:

is a fused pyrazolyl substituted by substituted aryl, substitutedaralkyl, substituted cycloalkyl or substituted heteroaryl;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R⁴ is alkyl and R^(b) is hydrogen;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl; and-   each R⁸ is independently selected from hydrogen or alkyl.

Of this embodiment, a first embodiment are compounds of formula (I)wherein:

is a fused pyrazolyl substituted by aryl substituted by one or moresubstituents selected from halo, —R¹⁰—OR¹¹ or —R¹⁰—C(O)R¹¹;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R⁴ is alkyl and R^(b) is hydrogen;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl;-   each R¹⁰ independently is a direct bond or a straight or branched    alkylene chain; and-   each R¹¹ is independently hydrogen, alkyl, cycloalkyl, optionally    substituted aryl, or optionally substituted heteroaryl.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   (4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone;-   (4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-8-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol    hydrochloride;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-2-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-2-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;    and-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol.

Of this embodiment, a second embodiment are compounds of formula (I)wherein:

is a fused pyrazolyl substituted by aralkyl substituted by one or moresubstituents selected from halo, —R¹⁰—OR¹¹ or —R¹⁰—C(O)R¹¹;

-   R¹ is hydrogen;-   R² is —R⁶—OR⁷;-   R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;-   R^(4a) is alkyl and R^(4b) is hydrogen;-   R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;-   each R⁶ is independently selected from a direct bond or a straight    or branched alkylene chain;-   each R⁷ is independently selected from hydrogen or alkyl;-   each R⁸ is independently selected from hydrogen or alkyl;-   each R¹⁰ is independently a direct bond or a straight or branched    alkylene chain; and-   each R¹¹ is independently hydrogen, alkyl, cycloalkyl or optionally    substituted aryl.

Of this embodiment, an embodiment are compounds of formula (I) selectedfrom:

-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;    and-   ((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.

It is understood that any embodiment of the compounds of the invention,as set forth above, and any specific substituent set forth herein for aparticular R group in the compounds of the invention, as set forthabove, may be independently combined with other embodiments and/orsubstituents of compounds of the invention to form embodiments of theinventions not specifically set forth above. In addition, in the eventthat a list of substituents is listed for any particular R group in aparticular embodiment and/or claim, it is understood that eachindividual substituent may be deleted from the particular embodimentand/or claim and that the remaining list of substituents will beconsidered to be within the scope of the invention.

Another embodiment of the invention are methods for treatinginflammation in the presence or absence of pain in a mammal in needthereof is where the inflammation is an autoimmune disease, disorder orcondition, an inflammatory disease, disorder or condition, or aneoplastic or cell proliferative disease, disorder or condition.

Another embodiment of the methods for treating inflammation in thepresence or absence of pain in a mammal in need thereof is where theinflammation is an autoimmune disease, disorder or condition selectedfrom idiopathic pulmonary fibrosis, an inflammatory bowel disease,rheumatoid arthritis, osteoarthritis, Still's Disease, Sjögren'sSyndrome, systemic lupus erythematosus, multiple sclerosis, psoriasisand systemic sclerosis.

Another embodiment of the methods for treating inflammation in thepresence or absence of pain in a mammal in need thereof is where theinflammation is an inflammatory bowel disease selected from Crohn'sDisease and ulcerative colitis.

Another embodiment of the methods for treating inflammation in thepresence or absence of pain in a mammal in need thereof is where theinflammation is an inflammatory disease, disorder or condition selectedfrom acute respiratory distress syndrome, allergic rhinitis, Alzheimer'sDisease, asthma, an ocular inflammatory disease, atopic dermatitis,bladder pain syndrome/interstitial cystitis, chronic prostatitis/chronicpelvic pain syndrome (CP/CPPS), chronic obstructive pulmonary disease(COPD) including emphysematous, bronchitic, and alpa 1 anti-trypsindeficiency related COPD; dermal contact hypersensitivy, eczema,eosiniphilic gastrointestinal disorder, fibromyalgia, gout, hepaticfibrosis, irritable bowl syndrome, ischemic reperfusion disease, kidneyfibrosis, pancreatitis, Parkisons Disease, post operative inflammation,a seronegative spondyloarthropathy, and vasculitis.

Another embodiment of the methods for treating inflammation in thepresence or absence of pain in a mammal in need thereof is where theinflammation is an ocular inflammatory disease selected from allergicconjunctivitis, dry eye, and uveitis.

Another embodiment of the methods for treating inflammation in thepresence or absence of pain in a mammal in need thereof is where theinflammation is a seronegative spondyloarthropathy selected fromanklyosing spondylitis, psoriatic arthritis, and Reiter's Syndrome.

Another embodiment of the methods for treating inflammation in thepresence or absence of pain in a mammal in need thereof is where theinflammation is vasculitis selected from Wegener's Granulomatosis,polyarteritis nodosa, leucocytoclastic vasculitis, Churg-StraussSyndrome, cryoglobulinemic vasculitis, and giant cell arteritis.

Another embodiment of the methods for treating inflammation in thepresence or absence of pain in a mammal in need thereof is where theinflammation is a neoplastic or cell proliferative disease, disorder orcondition selected from acute myelogenous leukemia, chronic myelogenousleukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia,basophilic leukemia, cutaneous T-cell lymphoma, Sezary Syndrome,Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,hypereosinophilic syndromes, mastocytosis and thrombocythemia.

Another embodiment of the methods for treating pain in a mammal in needthereof is where the pain is acute pain, chronic pain, inflammatorypain, nociceptive pain, inflammatory nociceptive pain, neuropathic painand any combinations thereof.

Another embodiment of the methods for treating pain in a mammal in needthereof is where the pain is in the absence or presence of inflammation.

Another embodiment of the invention is a method of using the compoundsof the invention as standards or controls in in vitro or in vivo assaysin determining the efficacy of test compounds in treating inflammationand/or pain.

In another embodiment of the invention, the compounds of the inventionare isotopically-labeled by having one or more atoms therein replaced byan atom having a different atomic mass or mass number. Suchisotopically-labeled (i.e., radiolabelled) compounds of the inventionare considered to be within the scope of this invention.

Examples of isotopes that can be incorporated into the compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but notlimited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P,³⁵S, ¹⁸F, ³⁸Cl, ¹²³I, and ¹²⁵I, respectively. These isotopically-labeledcompounds would be useful to help determine or measure the effectivenessof the compounds, by characterizing, for example, the site or mode ofaction for the modulation, or binding affinity to pharmacologicallyimportant site of action for the modulation. Certainisotopically-labeled compounds of the invention, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Synthetic Examples as set out below using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products are typically are identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

In other embodiments, preferred stereochemistry of the compounds offormula (I) is shown below:

Specific embodiments of the compounds of the invention are described inmore detail below in the Preparation of the Compounds of the Invention.

Utility and Testing of the Compounds of the Invention

Compounds and compositions of the invention are useful in treatinginflammation and/or pain. In particular, the compounds and compositionsof the invention may be used to treat inflammation in the absence ofpain, inflammation in the presence of pain or pain in the absence ofinflammation, preferably pain in the absence of visible inflammation.

Without being bound to any theory, and for the sole purpose of thisinvention, the term “inflammation” is intended to include, but notlimited to, an autoimmune disease, disorder or condition, aninflammatory disease, disorder or condition, or a neoplastic or cellproliferative disease, disorder or condition; idiopathic pulmonaryfibrosis, an inflammatory bowel disease, rheumatoid arthritis,osteoarthritis, Still's Disease, Sjögren's Syndrome, systemic lupuserythematosus, multiple sclerosis, psoriasis and systemic sclerosis;Crohn's Disease or ulcerative colitis; acute respiratory distresssyndrome, allergic rhinitis, Alzheimer's Disease, asthma, an ocularinflammatory disease, atopic dermatitis, bladder painsyndrome/interstitial cystitis, chronic prostatitis/chronic pelvic painsyndrome (CP/CPPS), chronic obstructive pulmonary disease (COPD)including emphysematous, bronchitic, and alpa 1 anti-trypsin deficiencyrelated COPD; dermal contact hypersensitivity, eczema, eosiniphilicgastrointestinal disorder, fibromyalgia, gout, hepatic fibrosis,irritable bowel syndrome, ischemic reperfusion disease, kidney fibrosis,pancreatitis, Parkinson's Disease, postoperative inflammation, aseronegative spondyloarthropathy or vasculitis; allergic conjunctivitis,dry eye or uveitis; ankylosing spondylitis, psoriatic arthritis orReiter's Syndrome; vasculitis selected from Wegener's Granulomatosis,polyarteritis nodosa, leucocytoclastic vasculitis, Churg-StraussSyndrome, cryoglobulinemic vasculitis or giant cell arteritis; aneoplastic or cell proliferative disease, disorder or condition selectedfrom acute myelogenous leukemia, chronic myelogenous leukemia, acutelymphocytic leukemia, chronic lymphocytic leukemia, basophilic leukemia,cutaneous T-cell lymphoma, Sezary Syndrome, Hodgkin's Disease,Non-Hodgkin's Lymphoma, multiple myeloma, hypereosinophilic syndromes,mastocytosis and thrombocythemia.

For the sole purpose of this invention, the term “pain” is intended toinclude acute pain, chronic pain, inflammatory pain, nociceptive pain,inflammatory nociceptive pain, neuropathic pain and any combinationsthereof. The types of pain intended to be treated by the compounds ofthe invention include, but are not limited to, pain associated with anyof the above disclosed inflammatory diseases, disorders and conditions,burn pain, chronic bone pain, low back pain, neck pain, abdominal pain,somatic pain, visceral pain, myofascial pain, dental pain, cancer pain,chemotherapy pain, temporomandibular joint pain, trauma pain, surgicalpain, post-surgical pain, labor pain, bladder pain, musculoskeletalpain, peripherally mediated pain, centrally mediated pain, headachepain, migraine pain, phantom limb pain, peripheral nerve injury pain,post-herpetic pain, non-cardiac chest pain, irritable bowel syndromepain, fibromyalgia and combinations thereof.

The effectiveness of the compounds of the invention in treatinginflammation and/or pain may be determined by any number of known invitro and in vivo assays, including the assays set forth below inBiological Examples 1-15.

For example, the compounds of the invention may be tested in thefollowing in vitro assays:

-   A. Rat or human dorsal root ganglion excitability assay (see, e.g.,    Young, G. T., et al., Mol. Ther. 22, 1530-43 (2014), and Tams, D.,    et al., Nature Methods 14 (2017)):    -   This assay measures the effect of electrical field stimulation        on the excitability of rat or human dorsal root ganglionic        cells. Compounds which demonstrate the ability to decrease the        excitability response of a cell when tested in this assay may be        useful in treating neuropathic pain.-   B. T-cell proliferation and cytokine release assay:    -   This assay measures the inflammatory response.-   C. Metabolism (microsomal stability) (see, e.g., Chiba, M, et al.,    AAPS J. 2009 11(2) 262):    -   This assay measures a compound's stability against microsomal        metabolism, which is a primary metabolic pathway: Compounds        tested in this assay which are relatively more stable than        others may be more effective in treating inflammation or pain.

Furthermore, the general value of the compounds of the of the inventionin treating inflammation and pain may be established in industrystandard animal models for demonstrating the efficacy of compounds intreating inflammation and pain.

Examples of these animal models are as follows:

-   A. Mouse LPS challenge (see, e.g., Kabir, K. et al., Shock, 2002,    17(4), 300-3): This is a well-known animal model for inflammation.-   B. Mouse formalin pain (see, e.g., Le Bars, D. et al., Pharmacol.    Rev. 2001, 53(4),597-652): This is a well-known model of    inflammatory and neuropathic pain.-   C. Rat TNBS Colitis (see, e.g., Antoniou, E., et al., Ann Med Surg    (Lond), 2016, 11, 9-15): This is a model for inflammatory colitis    and measures inflammatory response.-   D. Rat CYP Cystitis (see, e.g., Golubeva, A. V., et al., Physiol.    Rev., 2014, 2(3), e00260 and Keay, S., et al., BMC Urol, 2012, 12,    17):    -   This is a cyclophosphamide-induced cystitis model which measures        the effect on visceral/abdominal/pelvic pain. This is directly        supportive of use of the compounds for treating nociceptive        pain.-   E. Rat Ketamine cystitis (see, e.g., Jang, M.-Y., et al., Urological    Science, 28(3), 123-7, 2017):    -   This is a urogenital (upper and lower) model for pain.-   F. Rat Chronic Prostatitis/Chronic Pelvic Pain (see, e.g.,    Radhakrishnan, R. and Nallu, R. S., 2009, Inflammopharmacology, 17:    23-28):    -   This is a model for assessing a compounds ability to treat        prostatitis and prostate inflammatory pain.-   G. Rat MIA-induced osteoarthritis (see, e.g., Guingamp, C., et al.,    Arthritis and Rheumatism, 40(9), 1997, 1670-9):    -   This is a model for chronic nociceptive joint pain, which has        both an inflammatory component and a nociceptive component.-   H. Rat Carrageenan-induced hyperalgesia and paw edema (see, e.g.,    Morris, C.J., Methods Mol. Biol., 2003, 225, 115-21): This is an    inflammatory response model. It measures both inflammatory and pain    responses.-   I. Rat Complete Freund's Adjuvant model of inflammatory pain (see,    e.g., Fehrenbacher, J. C., et al., Curr. Protoc. Pharmacol., 2012    Mar, Chapter 5, Unit 5.4):    -   This is well-known model for inflammatory pain, particularly in        the joints.-   J. Rat Spinal nerve ligation model of neuropathic pain (see, e.g.,    Chung, J. M., et al., Methods in Molecular Medicine, 2004, 99,    35-45): This is a model for neuropathic pain.-   K. Mouse Bleomycin Lung Fibrosis Model (see, e.g., Moore, B. B., et    al., Am J Respir Cell Mol Biol, 2013, 49(2), 167-79): This is an    inflammatory response model.

Pharmaceutical Compositions of the Invention and Administration

For the purposes of administration, the compounds of the presentinvention may be formulated as pharmaceutical compositions.Pharmaceutical compositions comprise one or more compounds of thisinvention in combination with a pharmaceutically acceptable carrierand/or diluent. The compound is present in the composition in an amountwhich is effective to treat inflammation and/or pain, and preferablywith acceptable toxicity to the patient. Typically, the pharmaceuticalcompositions of the present invention may include a compound in anamount from 0.1 mg to 250 mg per dosage depending upon the route ofadministration, and more typically from 1 mg to 60 mg. Appropriateconcentrations and dosages can be readily determined by one skilled inthe art.

Pharmaceutically acceptable carrier and/or diluents are familiar tothose skilled in the art. For compositions formulated as liquidsolutions, acceptable carriers and/or diluents include saline andsterile water, and may optionally include antioxidants, buffers,bacteriostats and other common additives. The compositions can also beformulated as pills, capsules, granules, or tablets which contain, inaddition to a compound of this invention, diluents, dispersing andsurface active agents, binders, and lubricants. One skilled in this artmay further formulate the compounds in an appropriate manner, and inaccordance with accepted practices, such as those disclosed inRemington's Pharmaceutical Sciences (Mack Pub. Co., N.J. currentedition).

In another embodiment, the present invention provides a method fortreating inflammation and/or pain generally and, more specifically, totreating the diseases, disorders and conditions as discussed above. Suchmethods include administering of a compound of the present invention toa mammal, preferably a human, in an amount sufficient to treat theinflammation and/or pain. In this context, “treat” includes prophylacticadministration. Such methods include systemic administration of acompound of the invention, preferably in the form of a pharmaceuticalcomposition as discussed above. As used herein, systemic administrationincludes oral and parenteral methods of administration. For oraladministration, suitable pharmaceutical compositions include powders,granules, pills, tablets, and capsules as well as liquids, syrups,suspensions, and emulsions. These compositions may also includeflavorants, preservatives, suspending, thickening and emulsifyingagents, and other pharmaceutically acceptable additives. For parenteraladministration, the compounds of the present invention can be preparedin aqueous injection solutions which may contain buffers, antioxidants,bacteriostats, and other additives commonly employed in such solutions.

Preparation of the Compounds of the Invention

The General Reaction Schemes below illustrate methods to makeintermediates and compounds of the present invention, i.e., compounds offormula (I), as set forth above in the Summary of the Invention.

The compounds of the present invention may be prepared by known organicsynthesis techniques, including the methods described in more detail inthe Synthetic Examples. In general, the compounds of formula (I) may bemade by the following General Reaction Schemes, wherein all substituentsare as defined above in the Summary of the Invention unless indicatedotherwise. Although not generally depicted in the following schemes, oneskilled in the art will understand that appropriate protecting groupstrategies may be useful in preparing compounds of formula (I).Protecting group methodology is well known to those skilled in the art(see, for example, Greene, T. W. and Wuts, P.G.M. Greene's ProtectiveGroups in Organic Synthesis (latest edition). In particular, suitableprotecting groups for an oxygen atom (“oxygen protecting groups”)include, but are not limited to, acetyl, trialkylsilyl ordiarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitableprotecting groups for a nitrogen atom (“nitrogen protecting groups”)include, but are not limited to, benzhydryl (diphenylmethyl),t-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetate, and the like.

It is also understood that one skilled in the art would be able to makethe compounds of the invention by similar methods, by methods known toone skilled in the art, or by methods similar to the methods disclosedin U.S. Pat. Nos. 6,635,629, 7,601,874, and 9,765,085 and U.S. PublishedPatent Application No. 2017/0253596. It is also understood that oneskilled in the art would be able to make in a similar manner asdescribed below other compounds of the invention not specificallyillustrated below by using the appropriate starting components andmodifying the parameters of the synthesis as needed. In general,starting components may be obtained from sources such as Sigma Aldrich,Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, andFluorochem USA, etc. or synthesized according to sources known to thoseskilled in the art (see, e.g., Smith, M.B. and J. March, March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6thedition (Wiley, 2007)) or prepared as described herein. Certain startingmaterials, or their salts thereof, may be prepared according to themethods disclosed in U.S. Pat. Nos. 6,635,629, 7,601,874 and 9,765,085and U.S. Published Patent Application No. 2017/0253596, the relevantdisclosures therein are incorporated in reference herein, or by methodsknown to one skilled in the art.

It is also understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art, althoughprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

When a compound of the invention is depicted in the General ReactionSchemes below without stereochemistry, it is understood that one skilledin the art would readily recognize that such compounds could also beprepared in an optically pure form by utilizing methods known to oneskilled in the art, such as the use of stereoselective reagents, chiralstarting materials and phase transfer catalysts.

Abbreviations

The following abbreviations may be used herein in the following GeneralReaction Schemes and in the Synthetic Examples. If an abbreviation isnot included below, it is understood to have its accepted meaning in thefield to which it pertains:

-   Ac for acetyl;-   Ac₂O for acetic anhydride;-   ACN for acetonitrile-   AcOH for acetic acid;-   BALF for Bronchoalveolar lavage fluid;-   t-BuOH for tert-butanol;-   t-BuOOH or TBHP for tert-butyl hydroperoxide;-   CFA for Complete Freund's Adjuvant;-   CP/CPPS for chronic prostatitis/chronic pelvic pain syndrome;-   CSA for camphor sulfonic acid;-   DCM for dichloromethane;-   DMAP for 4-dimethylaminopyrdine;-   DMF for N,N-dimethylformamide;-   DMP for Dess-Martin periodinane:-   DMS for dimethyl sulphide;-   DMSO for dimethyl sulfoxide;-   DRG for Dorsal root ganglion;-   EFS for Electrical field stimulation;-   ELISA for enzyme-linked immunosorbent assay;-   ELSD for Evaporative Light Scattering Detection;-   Eq for equivalents;-   EtOAc for ethyl acetate;-   EtOH for ethanol;-   Fluo 8-AM for Bis(acetoxymethyl)    2,2′-((4-(6-(acetoxymethoxy)-3-oxo-3H-xanthen-9-yl)-2-(2-(bis(2-acetoxymethoxy)-2-oxoethyl)amino)phenoxy)ethoxy)phenyl)azanediyl)diacetate;-   h for hours;-   HCO₂Et for ethyl formate;-   IP for intraperitoneal;-   LiAlH₄ or LAH for lithium aluminum hydride;-   LiHMDS for lithium bis(trimethylsilyl)amide;-   LPS for Lipopolysaccharide;-   m or min for minutes;-   MeLi for methyllithium;-   MeOH for methanol;-   MIA for monosodium iodoacetate;-   Mn(OAc)₃ for manganese (Ill) acetate;-   MRM for multiple reaction monitoring;-   MS for Mass spectrometry;-   Ms for mesyl;-   MsCl for mesyl chloride;-   NADPH for the reduced form of nicotinamide adenine dinucleotide    phosphate;-   NaOMe for sodium methoxide;-   NMO for N-methylmorpholine N-oxide;-   NMR for nuclear magnetic resonance;-   Pet ether for petroleum ether,-   PPh₃ for triphenylphosphine;-   PhN(Tf)₂ for N-phenyl-bis(trifluoromethanesulfonimide);-   PhB(OH)₂ for phenyl boronic acid;-   Pd(PPh₃)₄ for tetrakis(triphenylphosphine)palladium(0);-   POCl₃ for phosphoryl chloride;-   RB for round-bottom;-   RT for room temperature;-   s for second;-   TBAF for tetrabutylammonium fluoride;-   TBDPS for tert-butyldiphenylsilyl;-   TBHP for tert-butyl hydroperoxide:-   TBS or TBDMS for tert-butyldimethylsilyl;-   TBSCl or TBDMSCl for tert-butyldimethylsilyl chloride;-   TEA for triethylamine;-   TFA for trifluoroacetic acid;-   THF for tetrahydrofuran;-   TLC for thin layer chromatography;-   TNBS for 2,4,6-trinitrobenzenesulfonic acid;-   TPAP for tetrapropylammonium perruthenate;-   t_(R) for retention time;-   TTX for tetrodotoxin;-   UHPLC for ultra high-pressure liquid chromatography; and-   UV for ultraviolet.

The following General Methods and Procedures were used to prepare,seperate or characterize individual compounds of the invention. It willbe appreciated that in the following general methods, reagent levels andrelative amounts or reagents/intermediates can be changed to suitparticular compounds to be synthesized, up or down by up to 50% withoutsignificant change in expected results.

1. General LC/MS Analytical Methods

Flow Method Column rate # Details A B (ml/min) T1 T2 T3 T4 T5 Ia A 0.1%TFA 0.1 % 1.5 Time 0 2.5 4.5 4.6 6 in water TFA in % B 10 95 95 10 10 IbB ACN 2 Time 0 8 8.1 8.5 10 % B 5 100 100 5 5 Ic B 0.1% TFA 0.1% 1.5Time 0 2.5 4 4.5 6 in TFA in % B 5 95 95 5 5 water:ACN ACN (95:5) Id C0.1% ACN 1.5 Time 0 2.5 4 4.5 6 formic in % B 5 95 95 5 5 water:ACN(95:5) Ie B 10 mM ACN 2 Time 0 4 5 5.5 6.5 NH₄HCO₃ % B 10 95 95 10 10 inwater 1f A 0.1% ACN 1.5 Time 0 3 5 5.5 6 formic acid % B 50 95 95 50 50in water 1g B 10 mM ACN 1 Time 0 8 8.1 8.5 10 NH₄HCO₃ % B 5 100 100 5 5in water 1h B 10 mM ACN 1.2 Time 0 2.5 5.0 5.5 7 NH₄HCO₃ % B 50 95 95 5050 in water 1i D ACN 0.1% 1.5 Time 0 2.5 4.5 4.6 6 formic % B 10 95 9510 10 acid in water 1j E 10 mM ACN 1.2 Time 0 2.5 5.0 5.5 7 NH₄HCO₃ % B50 95 95 50 50 in water 1k E 10 mM ACN 1.2 Time 0 3.5 4.5 5.0 6.0NH₄HCO₃ % B 10 95 95 10 10 in water 1l B 0.1% 0.1% 1.8 Time 0 2.5 7.07.1 8 formic in TFA in % B 80 98 98 80 80 water:ACN ACN (95:5) Colummdetails: A: Atlantis dC18 (50x4.6 mm, 5 μm), B: XBridge C8 (50x4.6 mm,3.5 μm), C: Zorbax XDB C18 (50x4.6 mm, 3.5 μm), D: Zorbax C18 (50x4.6mm, 5 μm), E: Zorbax Extend C18 (50x4.6 mm, 5 μm),

2. General HPLC Analytical Methods

Flow Method Column rate # Details A B (ml/min) T1 T2 T3 T4 T5 2a B 0.1%0.1% 2 Time 0 8 8.1 8.5 10 TFA in TFA in % B 5 100 100 5 5 water ACN 2bF 10 mM ACN 1 Time 0 15 20 26 30 NH₄HCO₃ % B 10 100 100 10 10 in water2c A 0.1% 0.1% 1.5 Time 0 8 8.1 8.5 10 TFA in TFA in % B 5 100 100 5 5water ACN 2d G 0.1% ACN 1 Time 0 15 20 26 30 TFA in % B 10 100 100 10 10water 2e B 10 mM ACN 1 Time 0 8 8.1 8.5 10 NH₄HCO₃ % B 5 100 100 5 5 inwater Columm details: A: Atlantis dC18 (50x4.6 mm, 5 μm), B: XBridge C8(50x4.6 mm. 3.5 μm), C: Zorbax XDB C18 (50x4.6 mm, 3.5 μm), F:Phenomenex Gemini C18 (150x4.6 mm, 3.0 μm), G: Atlantis dC18 (250x4.6mm, 5 μm)

3. General Preparative HPLC Methods

Method Column Flow rate # Details A B (ml/min) 3a H 0.1% TFA in water0.1% TFA 15 in ACN 3b H 0.1% formic acid in water: ACN 15 ACN (95:5) 3cI 10 mM NH₄OAc in water ACN 22 3d I Water ACN 22 3e H 0.1% TFA in waterACN 15 Columm details: H: Sunfire C18 (19 × 150 mm, 5 μm), I: YMC-triartC18 (30 × 250 mm, 5 μm)

General Procedure A Acetylation With Ac₂O

To a stirred solution of the alcohol (1 equivalent) in pyridine at 0° C.were added DMAP (0.05 equivalent) and Ac₂O (1 equivalent) and theresultant solution was stirred at ambient temperature. In a standardworkup, the mixture was concentrated under reduced pressure, dilutedwith EtOAc and washed consecutively with water and brine. The combinedorganic extracts were dried (Na₂SO₄ or MgSO₄), filtered and concentratedunder reduced pressure. The crude material was purified by flash columnchromatography on silica gel.

General Procedure B

TBS Protection of Alcohols

To a stirred solution of the alcohol (1 equivalent) in DMF at ambienttemperature was added imidazole (2 equivalents) followed by TBSCl (1equivalent) at 0° C. The resulting mixture was stirred at ambienttemperature. In a standard workup, the mixture was concentrated underreduced pressure, diluted with CH₂Cl₂ and washed consecutively withwater and brine. The combined organic extracts were dried (Na₂SO₄ orMgSO₄), filtered and concentrated under reduced pressure. The crudematerial was purified by flash column chromatography on silica gel.

General Procedure C Allylic Oxidation with TBHP/Cat

1. Option using Copper(I)Iodide

To a stirred solution of the alkene (1 equivalent) in CH₂Cl₂:ACN (1:1)at 0° C. were added (TBHP in decane (5 equivalents) and copper(I)iodide(0.1 equivalent) and the resultant mixture was stirred at ambienttemperature for 12 hours. In a standard workup, the mixture wasconcentrated under reduced pressure, diluted with EtOAc and washedconsecutively with water and brine. The combined organic extracts weredried (Na₂SO₄ or MgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by flash column chromatographyon silica gel.

2. Option using Manganese(III)Acetate Dihydrate:

To a stirred solution of the alkene (1 equivalent) in CH₂Cl₂:ACN:EtOAc(1:1:1) at room temperature were added TBHP in decane (5.2 equivalents)and 4 Å molecular sieves, the resultant mixture was stirred at roomtemperature for 0.5 hours. At this point, was added Mn(OAc)₃.2H₂O (0.1equivalent) and stirring was continued overnight at ambient temperature.In a standard workup, the mixture was filtered through a bed of CELITE®and the filtrate was concentrated under reduced pressure. The crudematerial was purified by flash column chromatography on silica gel.

3. Option Using Selenium Dioxide:

To a stirred solution of the alkene (1 equivalent) in CH₂Cl₂ at 0° C.were added TBHP in decane (5 equivalents) and SeO₂ (0.5 equivalent) andthe resultant mixture was stirred at ambient temperature for 12 hours.In a standard workup, the mixture was diluted with CH₂Cl₂ and washedconsecutively with water and brine. The combined organic extracts weredried (Na₂SO₄ or MgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by flash column chromatographyon silica gel.

General Procedure D Hydroboration Sequence

To a stirred solution of the ketone (1 equivalent) in THF at 0° C. wasadded Borane in THF (1 M, 2.23 equivalents). The resulting mixture wasstirred at same temperature for 12 hours. The mixture was quenched withdropwise addition of purified chilled water and stirred for 15 minutes.To the resulting mixture was added sodium perborate tetrahydrate atambient temperature and stirred for 3 hours. In a standard workup, themixture was diluted with EtOAc and washed consecutively with water andbrine. The combined organic extracts were dried (Na₂SO₄ or MgSO₄),filtered and concentrated under reduced pressure. The crude material waspurified by flash column chromatography on silica gel.

General Procedure E Ketal/Acetal Deprotection with AcOH

The Ketal/Acetal protected moiety (1 equivalent) was dissolved in 80%aqueous AcOH. The resulting mixture was heated to 65° C. and stirred for1 hour. In a standard workup, the mixture was concentrated under reducedpressure and diluted with saturated aqueous NaHCO₃. The aqueous wasextracted with CH₂Cl₂. The combined organic extracts were washed withbrine, dried (Na₂SO₄ or MgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by flash column chromatographyon silica gel.

General Procedure F NalO₄ Diol Cleavage

To a stirred solution of the alcohol (1 equivalent) in THF and water(2:1) at ambient temperature was added NalO₄ (2 equivalents). Theresulting mixture was stirred at room temperature for 1 hour. In astandard workup, the mixture was diluted with EtOAc and washedconsecutively with water and brine. The combined organic extracts weredried (Na₂SO₄ or MgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by flash column chromatographyon silica gel.

General Procedure G NaBH₄ Reduction of Carbonyls

To a stirred solution of the carbonyl compound (1 equivalent) in MeOH atroom temperature was added NaBH₄ (2 equivalents). The resulting mixturewas stirred at ambient temperature 4 hours. In a standard workup, themixture was concentrated under reduced pressure and diluted with EtOAcand washed consecutively with saturated aqueous NaHCO₃ and brine. Thecombined organic extracts were dried (Na₂SO₄ or MgSO₄), filtered andconcentrated under reduced pressure. The crude material was purified byflash column chromatography on silica gel.

General Procedure H Acetonide Formation with 2,2-dimethoxypropane

To a stirred solution of the diol (1 equivalent) in 2,2-dimethoxypropaneat 0° C. was added camphorsulphonic acid (0.1 equivalent). The resultingmixture was stirred at ambient temperature 2-4 hours. In a standardworkup, the mixture was concentrated under reduced pressure and dilutedwith EtOAc and washed consecutively with saturated aqueous NaHCO₃ andbrine. The combined organic extracts were dried (Na₂SO₄ or MgSO₄),filtered and concentrated under reduced pressure. The crude material waspurified by flash column chromatography on silica gel.

General Procedure I Mesylate Formation

To a stirred solution of the alcohol (1 equivalent) in pyridine at 0° C.was added MsCl (2 equivalents). The resulting mixture was stirred atambient temperature for 1 hour. In a standard workup, the mixture wasconcentrated under reduced pressure and diluted with EtOAc and washedconsecutively with water and brine. The combined organic extracts weredried (Na₂SO₄ or MgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by flash column chromatographyon silica gel.

General Procedure J Azide Introduction

To a stirred solution of the mesylate (1 equivalent) in DMF at ambienttemperature was added NaN₃ (3 equivalents). The resulting mixture wasstirred at 80° C. for 8 hours. In a standard workup, the mixture wasconcentrated under reduced pressure and diluted with EtOAc and washedconsecutively with water and brine. The combined organic extracts weredried (Na₂SO₄ or MgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by flash column chromatographyon silica gel.

General Procedure K K₂CO₃ Deprotection of Esters/TFA Amides

To the stirred solution of the ester/TFA-protected amide (1 equivalent)in MeOH at ambient temperature was added K₂CO₃ (2 equivalents) and fewdrops of water. The resulting mixture was heated to reflux for 2 hours.In a standard workup, the mixture was concentrated under reducedpressure and diluted with EtOAc and washed consecutively with water andbrine. The combined organic extracts were dried (Na₂SO₄ or MgSO₄),filtered and concentrated under reduced pressure. The crude material waspurified by flash column chromatography on silica gel.

General Procedure L TPAP/NMO Oxidation

To a stirred solution of the alcohol (1 equivalent) in CH₂Cl₂ at 0° C.were added NMO-H₂O (2 equivalents), 4 Å molecular sieves and TPAP (0.1equivalents). The resulting mixture was stirred at ambient temperaturefor 2 hours. In a standard workup, the mixture was diluted with CH₂Cl₂and filtered through a bed of CELITE® and the filtrate was concentratedunder reduced pressure. The crude material was purified by flash columnchromatography on silica gel.

General Procedure M Dess-Martin Periodinane Oxidation

To a stirred solution of the alcohol (1 equivalent) in CH₂Cl₂ at 0° C.was added Dess-Martin periodinane (2 equivalents). The resulting mixturewas stirred at ambient temperature for 2 hours. In a standard workup,the mixture was diluted with CH₂Cl₂ and washed consecutively withsaturated aqueous NaHCO₃ and brine. The combined organic extracts weredried (Na₂SO₄ or MgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by flash column chromatographyon silica gel.

General Procedure N Knoevenagel Condensation

To a stirred solution of the sodium hydride (60% dispersion in mineraloil) (4 equivalents) in THF at 0° C. was added the ketone in THF (1equivalent) dropwise. The resulting mixture was stirred at sametemperature for 2 hours. To the resulting mixture was added ethylformate (6 equivalents) at 0° C. and stirred at ambient temperature for8 hours. In a standard workup, the mixture was quenched with a saturatedaqueous solution of NH₄Cl and the aqueous layer extracted with EtOAc.The combined organic extracts were washed with brine, dried (Na₂SO₄ orMgSO₄), filtered and concentrated under reduced pressure. The crudematerial was purified by flash column chromatography on silica gel.

Alternative conditions for the Knoevenagel condensation include thefollowing: To a stirred solution of the ketone in toluene at 0° C. wereadded sodium methoxide solution (25% wt. in MeOH, 1.5-3 equivalents) andethyl formate (5-6 equivalents) dropwise and the resultant solutionstirred at ambient temperature for 16 hours. In a standard workup, themixture was concentrated under reduced pressure and diluted with chilledwater. The aqueous layer was extracted with EtOAc, washed with brine andthe organic layer dried (Na₂SO₄ or MgSO₄), filtered, concentrated andpurified by silica gel chromatography, if required.

General Procedure O Hydrazine Condensation to Form Pyrazoles

To a stirred solution of the ketone (1 equivalent) in EtOH at ambienttemperature was added hydrazine hydrate (2 equivalents) dropwise. Theresulting mixture was heated to 70° C. and stirred for 2 hours. In astandard workup, the mixture was concentrated under reduced pressure anddiluted with EtOAc and washed consecutively with water and brine. Thecombined organic extracts were dried (Na₂SO₄ or MgSO₄), filtered andconcentrated under reduced pressure. The crude material was purified byflash column chromatography on silica gel.

General Procedure P TBS Deprotection with TBAF

The TBS silyl ether (1 equivalent) was dissolved in THF and TBAF (1 M inTHF, 2 equivalents) was added at ambient temperature. The mixture washeated to 65° C. and stirred for 2 hours. In a standard workup, themixture was diluted with EtOAc and washed consecutively with water andbrine. The combined organic extracts were dried (Na₂SO₄ or MgSO₄),filtered and concentrated under reduced pressure. The crude material waspurified by flash column chromatography on silica gel.

General Procedure Q Azide Reduction with PPh₃

To a stirred solution of the azide (1 equivalent) in THF and water (9:1)at ambient temperature was added PPh₃ (2 equivalents). The mixture washeated to 60° C. and stirred for 4 hours. In a standard workup, themixture was diluted with EtOAc and washed consecutively with water andbrine. The combined organic extracts were dried (Na₂SO₄ or MgSO₄),filtered and concentrated under reduced pressure. The crude material waspurified by flash column chromatography on silica gel.

General Procedure R Azide Reduction with Lithium Aluminum Hydride

To a stirred solution of the azide (1 equivalent) in THF at 0° C. wasadded LAH (1 M in THF, 2 equivalents) dropwise. The mixture was stirredat room temperature for 4 hours. In a standard workup, the mixture wasquenched with saturated solution of Na₂SO₄ and filtered through a bed ofCELITE®, the aqueous was extracted with EtOAc. The combined organicextracts were washed with brine, dried (Na₂SO₄ or MgSO₄), filtered andconcentrated under reduced pressure. The crude material was purified byflash column chromatography on silica gel.

General Procedure S Pd-Catalyzed Hydrogenation of Double Bonds

To a stirred solution of the alkene (1 equivalent) in EtOAc at roomtemperature was added 10% Pd/C (˜5-10% of alkene weight) under anitrogen atmosphere. The mixture was stirred at room temperature for 2-4hours under 1 hydrogen atmosphere using a balloon. In a standard workup,the mixture was filtered through a bed of CELITE® and filtrate wasconcentrated under reduced pressure. The crude material was purified byflash column chromatography on silica gel.

General Procedure T HCl Salt Formation

To a stirred solution of amine (1 equivalent) in MeOH at 0° C. was addedHCl solution (2 M) in diethyl ether (5 volumes) and the resultantsolution was stirred at 0° C. for 1 hour. The mixture was concentratedunder reduced pressure. Diethyl ether was added, the solution wasstirred for 10 minutes and filtered. The resulting compound was allowedto dry for approx. 1 hour.

General Reaction Schemes

The following General Reaction Schemes illustrate methods to makecompounds of formula (I), or stereoisomers, enantiomers or tautomersthereof or mixtures thereof, or pharmaceutically acceptable salts orsolvates thereof, as set forth above in the Summary of the Invention.

General Reaction Scheme 1

Compounds of formula (I-1) are compounds of formula (I), as describedabove in the Summary of the Invention, and may be prepared according thefollowing General Reaction Scheme 1 wherein R⁵ is as described above inthe Summary of the Invention, R^(4a) and R¹ together form an optionallysubstituted bicyclic heterocyclyl, R^(4b) is hydrogen, Pg¹ is an oxygenprotecting group, such as tert-butydimethylsilyl ortert-butyldiphenylsilyl and X is halo, preferably chloro:

Compounds of formula (A) are commercially available, such as diosgenin,or may be prepared accordingly to methods known to one skilled in theart.

In general, compounds of formula (I-1) are prepared by first treating acompound of formula (A) under appropriate under appropriate GeneralProcedure B conditions to yield a compound of formula (B), which is thentreated under appropriate General Procedure C conditions to yield acompound of formula (C), which is then treated under appropriate GeneralProcedure D conditions to yield a compound of formula (D), when is thentreated with 2,2-dimethoxypropane under appropriate General Procedure Hconditions to yield a compound of formula (E), which is then treatedunder appropriate General Procedure P conditions to yield a compound offormula (F), which is then oxidized under appropriate General ProcedureM conditions to yield a compound of formula (G), which is then treatedunder appropriate General Procedure N conditions to yield a compound offormula (H), when is then treated with hydrazine hydrate underappropriate General Procedure O conditions to yield a compound offormula (J), when is then treated under appropriate General Procedure Econditions to yield a compound of formula (K), when is then treatedunder appropriate General Procedure F conditions to yield a compound offormula (L), which is then treated under appropriate General Procedure Gconditions to yield a compound of formula (I-1).

An embodiment of General Reaction Scheme 1 is described in more detailbelow in Synthetic Example 1.

General Reaction Scheme 2

Compounds of formula (I-2) are compounds of formula (I), as describedabove in the Summary of the Invention, and may be prepared according thefollowing General Reaction Scheme 2 wherein R⁵ is as described above inthe Summary of the Invention, R^(4a) and R¹ together form an optionallysubstituted bicyclic heterocyclyl and R^(4b) is hydrogen:

Compounds of formula (I-1) are prepared herein in Reaction Scheme 1 andin Synthetic Example 1.

In general, compounds of formula (I-2) are prepared by first treating acompound of formula (I-1) under the appropriate General Procedure Aconditions to yield a compound of formula (M), which is then treatedunder the appropriate General Procedure I conditions to yield a compoundof formula (N), which is then treated under the appropriate GeneralProcedure J conditions to yield a compound of formula (O), when is thentreated under the appropriate General Procedure R conditions to yieldthe compound of formula (I-2).

An embodiment of General Reaction Scheme 2 is described in more detailbelow in Synthetic Example 2.

General Reaction Scheme 3

Compounds of formula (I-3) are compounds of formula (I), as describedabove in the Summary of the Invention, and may be prepared according thefollowing General Reaction Scheme 3 wherein R¹ is hydrogen, R⁵ ismethyl, R^(b) is hydrogen, alkyl or optionally substituted heteroaryl,Pg¹ is an oxygen protecting group, such as tert-butydimethylsilyl ortert-butyldiphenylsilyl and X is halo, preferably chloro:

Compounds of formula (P) may be prepared according to the methodsdisclosed in U.S. Pat. No. 6,046,185, or by methods known to one skilledin the art.

In general, compounds of formula (I-3) are prepared by first treating acompound of formula (P) under the appropriate General Procedure Bconditions to yield a compound of formula (Q), which is then treatedwith R^(4a)Li under standard reduction conditions to yield a compound offormula (R), which is then treated under appropriate General Procedure Pconditions to yield a compound of formula (S), which is then treatedunder appropriate General Procedure M conditions to yield a compound offormula (T), which is then treated under appropriate General Procedure Nconditions to yield a compound of formula (U), which is then treatedunder appropriate General Procedure O conditions to yield a compound offormula (V), which is then treated under appropriate General Procedure Econditions to yield a compound of formula (W), which is then treatedunder appropriate General Procedure F conditions to yield a compound offormula (X), which is then treated under appropriate General Procedure Gconditions to yield a compound of formula (I-3).

An embodiment of General Reaction Scheme 3 is described in more detailbelow in Synthetic Example 3 and Synthetic Example 8.

Alternatively, when R^(4b) is an optionally substituted heteroaryl, thecompound of formula (S) can be treated under appropriate GeneralProcedure L conditions to form a compound of formula (T), when is thetreated as described above to form a compound of formula (I-3).

An embodiment of this alternate reaction scheme is described in moredetail below in Synthetic Example 4.

General Reaction Scheme 4

Compounds of formula (I-4) are compounds of formula (I), as describedabove in the Summary of the Invention, and may be prepared according thefollowing General Reaction Scheme 4 wherein R¹ is hydrogen, R⁵ is asdescribed above in the Summary of the Invention, R^(4a) is optionallysubstituted aryl, and Pg¹ is an oxygen protecting group, such astert-butydimethylsilyl or tert-butyldiphenylsilyl:

Compounds of formula (Q) may be prepared according to the methodsdisclosed herein or by methods known to one skilled in the art.

In general, compounds of formula (I-4) are prepared by first treating acompound of formula (Q) under appropriate enol triflate formationconditions to yield the compound of formula (Y), which is then treatedwith R^(4a)B(OH) under the appropriate cross coupling conditions toyield a compound of formula (Z), which is then treated under theappropriate General Procedure P conditions to yield a compound offormula (AA), which is then treated under the appropriate GeneralProcedure L conditions to yield a compound of formula (BB), which isthen treated under the appropriate General Procedure N conditions toyield a compound of formula (CC), which is then treated under theappropriate General Procedure O conditions to yield a compound offormula (DD), which is then treated under the appropriate GeneralProcedure E conditions to yield a compound of formula (EE), which isthen treated under the appropriate General Procedure F conditions toyield a compound of formula (FF), which is then treated under theappropriate General Procedure G conditions to yield a compound offormula (I-4).

An embodiment of General Reaction Scheme 4 is described in more detailbelow in Synthetic Example 5.

General Reaction Scheme 5

Compounds of formula (I-5) are compounds of formula (I), as describedabove in the Summary of the Invention, and may be prepared according thefollowing General Reaction Scheme 5 wherein R¹ is hydrogen, R⁵ is asdescribed above in the Summary of the Invention, R^(4a) is optionallysubstituted aryl, Pg¹ is an oxygen protecting group, such astert-butydimethylsilyl or tert-butyldiphenylsilyl and X is halo,preferably chloro:

Compounds of formula (I-4) may be prepared according to the methodsdisclosed herein or by methods known to one skilled in the art.

In general, compounds of formula (I-5) are prepared by first treating acompound of formula (I-4) under the appropriate General Procedure Bconditions to yield a compound of formula (GG), which is then treatedunder the appropriate General Procedure I conditions to yield a compoundof formula (HH), which is then treated under the appropriate GeneralProcedure J conditions to yield a compound of formula (II), which isthen treated under the appropriate General Procedure P conditions toyield a compound of formula (JJ), which is then treated under theappropriate General Procedure Q conditions to yield a compound offormula (I-5).

An embodiment of General Reaction Scheme 5 is described in more detailbelow in Synthetic Example 6.

General Reaction Scheme 6

Compounds of formula (I-6) are compounds of formula (I), as describedabove in the Summary of the Invention, and may be prepared according thefollowing General Reaction Scheme 6 wherein R¹ is hydrogen, R⁵ is asdescribed above in the Summary of the Invention Pg¹ is an oxygenprotecting group, such as tert-butydimethylsilyl ortert-butyldiphenylsilyl and X is halo, preferably chloro:

Compounds of formula (KK) may be prepared according to the methodsdisclosed in U.S. Pat. No. 7,601,874 or by methods known to one skilledin the art.

In general, compounds of formula (I-6) are prepared by first treating acompound of formula (KK) under appropriate General Procedure Bconditions to yield a compound of formula (LL), which is then treatedunder appropriate General Procedure I conditions to yield a compound offormula (MM), which is then treated under appropriate General ProcedureJ conditions to yield a compound of formula (NN), which is then treatedunder appropriate General Procedure K conditions to yield a compound offormula (OO), which is then treated under appropriate General ProcedureL conditions to yield a compound of formula (PP), which is then treatedunder appropriate ozonolysis conditions to yield a compound of formula(QQ), which is then treated under appropriate General Procedure Nconditions to yield a compound of formula (RR), which is then treatedunder appropriate General Procedure O conditions to yield a compound offormula (SS), which is then treated under appropriate General ProcedureP conditions to yield a compound of formula (TT), which is then treatedunder appropriate General Procedure R conditions to yield a compound offormula (I-6).

An embodiment of General Reaction Scheme 6 is described in more detailbelow in Synthetic Example 7.

General Reaction Scheme 7

Compounds of formula (I-7) are compounds of formula (I), as describedabove in the Summary of the Invention, and may be prepared according thefollowing General Reaction Scheme 7 wherein R¹ and R⁵ are as definedabove in the Summary of the Invention, Pg¹ is an oxygen protectinggroup, such as tert-butydimethylsilyl or tert-butyldiphenylsilyl, and Xis halo, preferably chloro:

Compounds of formula (UU), such as stigmasterol, are commerciallyavailable or can be prepared accordingly to methods known to one skilledin the art.

In general, compounds of formula (I-7) are prepared by first treating acompound of formula (UU) under the appropriate General Procedure Bconditions to yield a compound of formula (VV), which is then treatedunder the appropriate General Procedure C conditions to yield a compoundof formula (WW), which is then treated under the appropriate GeneralProcedure D conditions to yield a compound of formula (XX), which isthen treated under the appropriate General Procedure H conditions toyield a compound of formula (YY), which is then treated under theappropriate General Procedure A conditions to yield a compound offormula (ZZ), which is then treated under the appropriate GeneralProcedure P conditions to yield a compound of formula (AAA), which isthen treated under the appropriate General Procedure L conditions toyield a compound of formula (BBB), which is then treated under theappropriate General Procedure N conditions to yield a compound offormula (CCC), which is then treated under the appropriate GeneralProcedure O conditions to yield a compound of formula (DDD), which isthen treated under the appropriate General Procedure E conditions toyield a compound of formula (EEE), which is then treated under theappropriate General Procedure F conditions to yield a compound offormula (FFF), which is then treated under the appropriate GeneralProcedure G conditions to yield a compound of formula (I-7).

An embodiment of General Reaction Scheme 7 is described in more detailbelow in Synthetic Example 9.

General Reaction Scheme 8

Compounds of formula (I-8) are compounds of formula (I), as describedabove in the Summary of the Invention, and may be prepared according thefollowing General Reaction Scheme 8 wherein R¹ and R⁵ are as definedabove in the Summary of the Invention:

Compounds of formula (GGG) may be prepared according to the methodsdisclosed in U.S. Pat. No. 9,765,085 or by methods known to one skilledin the art.

In general, compounds of formula (I-8) are prepared by first treating acompound of formula (GGG) under standard osmium tetroxide-catalyzedperiodate oxidation conditions to yield a compound of formula (HHH),which is then treated under appropriate General Procedure G conditionsto yield a compound of formula (I-8), which is a mixture of enantiomerswhich can be isolated by standard resolution techniques.

An embodiment of General Reaction Scheme 8 is described in more detailbelow in Synthetic Example 10.

General Reaction Scheme 9

Compounds of formula (I-9) are compounds of formula (I), as describedabove in the Summary of the Invention, and may be prepared according thefollowing General Reaction Scheme 9 wherein R⁵ is as described above inthe Summary of the Invention, each Pg¹ is an oxygen protecting group,such as tert-butydimethylsilyl or tert-butyldiphenylsilyl and X is halo,preferably chloro:

Compounds of formula (KK) may be prepared according to the methoddisclosed herein or by methods known to one skilled in the art.

In general, compounds of formula (I-9) are prepared by first treating acompound of formula (KK) under appropriate General Procedure Bconditions to yield a compound of formula (III), which is then treatedunder appropriate General Procedure K conditions to yield a compound offormula (JJJ), which is then treated under appropriate General ProcedureL conditions to yield a compound of formula (KKK), which is then treatedunder appropriate ozonolysis conditions to yield a compound of formula(LLL), which is then treated under appropriate General Procedure Nconditions to yield a compound of formula (MMM), which is then treatedunder appropriate General Procedure O conditions to yield a compound offormula (NNN), which is then treated under appropriate General ProcedureP conditions to yield a compound of formula (I-9).

An embodiment of General Reaction Scheme 9 is described in more detailbelow in Synthetic Example 11.

General Reaction Scheme 10

Compounds of formula (I-10a) and formula (I-10b) are compounds offormula (I), as described above in the Summary of the Invention, and maybe prepared according the following General Reaction Scheme 10 whereinR¹ and R⁵ is as described above in the Summary of the Invention, Pg¹ isan oxygen protecting group, such as tert-butydimethylsilyl ortert-butyldiphenylsilyl, and R¹² is a substituted aryl, a substitutedaralkyl, a substituted cycloalkyl or a substituted heteroaryl, eachsubstituted by one or more substituents selected from halo, —R¹⁰OR¹¹ or—R¹⁰—C(O)R¹¹ where R¹⁰ is a direct bond or a straight or branchedalkylene chain; and R¹¹ is hydrogen, alkyl, cycloalkyl or optionallysubstituted aryl:

Compounds of formula (PPa) may be prepared according to the methodsdisclosed herein or by methods known to one skilled in the art.

In general, compounds of formula (I-10a) and (I-10b) are prepared byfirst treating a compound of formula (PP) under appropriate GeneralProcedure N conditions to yield a compounds of formula (OOO), which isthen treated with the appropriately substituted hydrazine under GeneralProcedure O conditions to yield a mixture of a compound of formula(PPPa) and a compound of formula (PPPb), which is then treated underappropriate General Procedure P conditions to yield a mixture of acompound of formula (QQQa) and a compound of formula (QQQb), which isthen treated under the appropriate General Procedure Q conditions toyield a mixture of a compound of formula (I-10a) and a compound offormula (I-10b).

Alternatively, a compound of formula (PPPa) or a compound of formula(PPPb) may be isolated from the mixture of the compound of formula(PPPa) and the compound of formula (PPPb) under standard isolationmethods known to one skilled in the art, and then treated underappropriate General Procedure P conditions to yield a compound offormula (QQQa) or a compound of formula (QQQb). The resulting compoundof formula (QQQa) or the compound of formula (QQQb) may then be treatedunder appropriate General Procedure Q conditions to yield a compound offormula (I-10a) or a compound of formula (I-10b).

Alternatively, a compound of formula (QQQa) or a compound of formula(QQQb) may be isolated from the mixture of the compound of formula(QQQa) and the compound of formula (QQQb) under standard isolationmethods known to one skilled in the art, and then treated underappropriate General Procedure Q conditions to yield a compound offormula (I-10a) or a compound of formula (I-10b).

Alternatively, a compound of formula (I-10a) or a compound of formula(I-10b) may be isolated from the mixture of the compound of formula(I-10a) and the compound of formula (I-10b) under standard isolationtechniques known to one skilled in the art.

Embodiments of General Reaction Scheme 10 and the above alternateisolation processes are described in more detail below in SyntheticExample 12 and in Examples 12.1 to 12.14.

General Reaction Scheme 11

Compounds of formula (I-11a) and (I-11b) are compounds of formula (I),as described above in the Summary of the Invention, and may be preparedaccording the following General Reaction Scheme 11 wherein R¹ ishydrogen, R⁵ is as described above in the Summary of the Invention, andPg¹ is an oxygen protecting group, such as tert-butydimethylsilyl ortert-butyldiphenylsilyl:

Compounds of formula (Q) may be prepared according to the methodsdisclosed herein or by methods known to one skilled in the art.

In general, compounds of formula (I-11a) and (I-11b) are prepared byfirst treating a compound of formula (Q) under standard oxime formationconditions to yield a compound of formula (RRR), which is then treatedunder the appropriate General Procedure E conditions to yield a compoundof formula (SSS), which is then treated under the appropriate GeneralProcedure A conditions to yield a compound of formula (TTT), which isthen treated under the appropriate reductive acylation conditions toyield a compound of formula (UUU), which is then treated undercyclization conditions to yield a compound of formula (VVV), which isthen treated under the appropriate General Procedure L conditions toyield a compound of formula (WWW), which is then treated under theappropriate General Procedure N conditions to yield a compound offormula (XXX), which is then treated under the appropriate GeneralProcedure O conditions to yield a compound of formula (YYY), which isthen treated under standard reductive dehalogenation conditions to yielda compound of formula (ZZZ), which is then treated under the appropriateGeneral Procedure F conditions to yield a compound of formula (AAAA),which is then treated under the appropriate General Procedure Gconditions to yield a compound of formula (I-11a), which is then firsttreated under appropriate General Procedure B conditions, then treatedunder appropriate General Procedure I conditions, then treated underappropriate General Procedure J conditions, then treated underappropriate General Procedure P conditions and then treated understandard Pd catalyzed reduction conditions to yield a compound offormula (I-11b).

An embodiment of General Reaction Scheme 11 is described in more detailbelow in Synthetic Example 13.

General Reaction Scheme 12

Compounds of formula (I-12a) and (I-12b) are compounds of formula (I),as described above in the Summary of the Invention, and may be preparedaccording the following General Reaction Scheme 12 wherein R⁵ is asdescribed above in the Summary of the Invention, Pg¹ is an oxygenprotecting group, such as tert-butydimethylsilyl ortert-butyldiphenylsilyl, X is halo, preferably chloro, and R¹² is asubstituted aryl, a substituted aralkyl, a substituted cycloalkyl or asubstituted heteroaryl, each substituted by one or more substituentsselected from halo, —R¹⁰—OR¹¹ or —R¹⁰—C(O)R¹¹ where R¹⁰ is a direct bondor a straight or branched alkylene chain; and R¹¹ is hydrogen, alkyl,cycloalkyl or optionally substituted aryl:

Compounds of formula (KK) may be prepared according to the methodsdisclosed herein or by methods known to one skilled in the art.

In general, compounds of formula (I-12a) and formula (I-12b) areprepared by first treating a compound of formula (KK) under standard Pdcatalyzed hydrogenation conditions to yield a compound of formula(BBBB), which is then treated under appropriate General Procedure Bconditions to yield a compound of formula (CCCC), which is then treatedunder appropriate General Procedure I conditions to yield a compound offormula (DDDD), which is then treated under appropriate GeneralProcedure J conditions to yield a compound of formula (EEEE), which isthen treated under appropriate General Procedure K conditions to yield acompound of formula (FFFF), which is then treated under appropriateGeneral Procedure L conditions to yield a compound of formula (GGGG),which is then treated under appropriate General Procedure N conditionsto yield a compound of formula (HHHH), which is then treated underappropriate General Procedure O conditions to yield a mixture of acompound of formula (IIIIa) and a compound of formula (IIIIb), which isthen treated under appropriate General Procedure P conditions, followedby treatment under appropriate General Procedure R conditions to yield amixture of a compound of formula (I-12a) and a compound of formula(I-12b).

Alternatively, a compound of formula (IIIIa) or a compound of formula(IIIIb) may be isolated from the mixture of the compound of formula(IIIIa) and the compound of formula (IIIIb) under standard isolationmethods known to one skilled in the art, and then treated underappropriate General Procedure Q conditions to yield a compound offormula (I-12a) or a compound of formula (I-12b).

Alternatively, a compound of formula (I-12a) or a compound of formula(I-12b) may be isolated from the mixture of the compound of formula(I-12a) and the compound of formula (I-12b) under standard isolationtechniques known to one skilled in the art.

Embodiments of General Reaction Scheme 12 are described in more detailbelow in Synthetic Examples 14-14.3.

All of the compounds described herein as being prepared which may existin free base or acid form may be converted to their pharmaceuticallyacceptable salts by treatment with the appropriate inorganic or organicbase or acid. Salts of the compounds prepared below may be converted totheir free base or acid form by standard techniques. Furthermore, allcompounds of the invention which contain an acid or an ester group canbe converted to the corresponding ester or acid, respectively, bymethods known to one skilled in the art or by methods described herein.

Representative compounds of the invention which were prepared by themethods disclosed herein include (but are not limited to) the compoundslisted below in Table 1. The compound (Cpd) numbers in this tablecorrespond to the compound numbers in Synthetic Examples 1-14.3 below.

TABLE 1 Cpd No. Compound Name Ia-1  ((5R, 6S)-5-((2R, 3S, 3aR, 3bS, 5′R,6S, 7R, 7aS, 8aS)-7-(hydroxymethyl)-3, 3b, 5′-trimethyltetradecahydrospiro[indeno [2, 1-b]furan-2, 2′-pyran]-6-yl)-5-methyl-4, 5, 6, 7-tetrahydro- 1H-indazol-6-yl)methanol Ia-2  ((5R,6S)-5-((2R, 3S, 3aR, 3bS, 5′R, 6S, 7R, 7aS, 8aS)-7-(aminomethyl)-3, 3b,5′- trimethyltetradecahydrospiro[indeno [2, 1-b]furan-2, 2′-pyran]-6-yl)-5-methyl-4, 5, 6, 7-tetrahydro- 1H-indazol-6-yl)methanol Ia-3  (1S,3aS, 4R, 5S, 7aS)-4-(hydroxymethyl)- 5-((5R, 6S)-6-(hydroxymethyl)-5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-5-yl)- 1,7a-dimethyloctahydro-1H-inden-1-ol Ia-4  (1S, 3aS, 4R, 5S,7aS)-4-(hydroxymethyl)- 5-((5R, 6S)-6-(hydroxymethyl)- 5-methyl-4, 5, 6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol Ia-5  ((5R,6S)-5-((3aS, 6S, 7R, 7aS)-7-(hydroxymethyl)- 3a-methyl-3-phenyl-3a, 4,5, 6, 7, 7a-hexahydro- 1H-inden-6-yl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-6  ((5R, 6S)-5-((3aS, 6S, 7R,7aS)-7-(aminomethyl)- 3a-methyl-3-phenyl-3a, 4, 5, 6, 7, 7a-hexahydro-1H-inden-6-yl)-5-methyl-4, 5, 6, 7- tetrahydro-1H-indazol-6-yl) methanolIa-7  ((5R, 6S)-5-((4aS, 5R, 6S, 8aS)-5-(aminomethyl)- 8a-methyl-1, 4,4a, 5, 6, 7, 8, 8a-octahydroindeno [1, 2-c]pyrazol-6-yl)-5-methyl- 4, 5,6, 7-tetrahydro-1H-indazol-6-yl)methanol Ia-8  (1S, 3aS, 4R, 5S,7aS)-4-(hydroxymethyl)- 5-((5R, 6S)-6-(hydroxymethyl)- 5-methyl-4, 5, 6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol Ia-9  (2S,5R)-5-ethyl-2-((1R, 3aS, 4S, 5S, 7aS)-4- (hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)- 5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-yl)- 6-methylheptan-3-ol Ia-10a (1S, 3aS,4R, 5S, 7aS)-4-(hydroxymethyl)- 5-((5R, 6S)-6-(hydroxymethyl)-5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol Ia-10b (1R, 3aS, 4R, 5S,7aS)-4-(hydroxymethyl)- 5-((5R, 6S)-6-(hydroxymethyl)- 5-methyl-4, 5, 6,7-tetrahydro-1H-indazol-5-yl)- 7a-methyloctahydro-1H-inden-1-ol Ia-11((4aS, 5R, 6S, 8aS)-6-((5R, 6S)-6-(hydroxymethyl)- 5-methyl-4, 5, 6,7-tetrahydro-1H-indazol- 5-yl)-8a-methyl-1, 4, 4a, 5, 6, 7, 8, 8a-octahydroindeno[1, 2-c]pyrazol-5-yl)methanol Ia-12 ((5R, 6S)-5-((3aS,4R, 5S, 7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-6-yl)methanol Ia-13 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-14 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-methoxyphenyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-15 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-16 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-17 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-18 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorobenzyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-19 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorobenzyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-20 (4-((5R, 6S)-5-((3aS, 4R,5S, 7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl- 4, 5, 6, 7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone Ia-21 (4-((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-2- yl)phenyl)(phenyl)methanone Ia-22 ((5R,6S)-5-((3aS, 4R, 5S, 7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-5-yl)-1-(3,4-difluorophenyl)-5- methyl-4, 5, 6, 7-tetrahydro-1H-indazol-6-yl)methanol Ia-23 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3, 4-difluorophenyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-24 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-25 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-26 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyrimidin-2-yl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-27 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyrimidin-2-yl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-28 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-1-(4-phenoxyphenyl)- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-29 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-2-(4-phenoxyphenyl)- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-30 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyridin-2-yl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-31 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyridin-2-yl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-32 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2-fluorophenyl)-5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-6-yl)methanol Ia-33 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2-fluorophenyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-34 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2, 4-difluorophenyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-35 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2, 4-difluorophenyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-36 4-(4-((5R, 6S)-5-((3aS, 4R,5S, 7aS)-4-(aminomethy)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-1-yl)phenoxy)benzoic acid Ia-37 4-(4-((5R,6S)-5-((3aS, 4R, 5S, 7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1 H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4, 5, 6, 7-tetrahydro-2H-indazol-2-yl)phenoxy)benzoic acid Ia-38 ((5R, 6S)-5-((3aS,4R, 5S, 7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1 H-inden-5-yl)-1-(4, 4-difluorocyclohexyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-39 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4, 4-difluorocyclohexyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-40 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3-fluorophenyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-41 ((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3-fluorophenyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-42 (1S, 3aS, 4R, 5S,7aS)-4-(aminomethyl)-5-((5R, 6S)- 6-(hydroxymethy)-5-methyl-4, 5, 6,7-tetrahydro- 1H-indazol-5-yl)-7a-methyl-1-(thlazol-2-yl)octahydro-1H-inden-1-ol Ia-43 ((5aS, 6R, 7S, 9aS)-7-((5R,6S)-6-(hydroxymethyl)- 5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-5-yl)-9a-methyl-5a, 6, 7, 8, 9, 9a-hexahydro-5H-indeno[1,2-b]pyridin-6-yl)methanol Ia-44 ((5R, 6S)-5-((5aS, 6R, 7S,9aS)-6-(aminomethyl)- 9a-methyl-5a, 6, 7, 8, 9, 9a-hexahydro-5H-indeno[1,2-b]pyridin-7-yl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-45 (4-((5R, 6S)-5-((1S, 3aS,4S, 5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone Ia-46 (4-((5R,6S)-5-(1S, 3aS, 4S, 5S, 7R)-4-(aminomethyl)- 1,7a-dimethyloctahydro-1H-inden-5-yl)- 6-(hydroxymethyl)-5-methyl-4, 5, 6,7-tetrahydro- 2H-indazol-2-yl)phenyl)(phenyl)methanone Ia-47 ((5R,6S)-5-((1S, 3aS, 4S, 5S, 7aR)-4- (aminomethyl)-1,7a-dimethyloctahydro-1H-inden- 5-yl)-1-(4-fluorophenyl)-5-methyl- 4, 5,6, 7-tetrahydro-1H-indazol-6-yl)methanol Ia-48 ((5R, 6S)-5-((1S, 3aS,4S, 5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-49 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxyphenyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-50 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-51 ((5R, 6S)-5-((1S, 3aS, 4S,5S,7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-52 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-53 (1S, 3aS, 4R, 5S,7aS)-4-(aminomethy)-5- ((5R, 6S)-6-(hydroxymethyl)-5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol Ia-54 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (amiriomethyl)-1, 7a-dimethyioctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)- 5-methyl-4, 5, 6,7-tetrahydro-2H- indazol-6-yl)methanol Ia-55 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)- 5-methyl-4, 5, 6, 7-tetrahydro-1H-indazol-6-yl)methanol Ia-55HCl ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (aminomethyl)-1 ,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)- 5-methyl-4, 5, 6,7-tetrahydro-1H-indazol- 6-yl)methanol hydrochloride Ia-56 ((5R,6S)-5-((1S, 3aS, 4S, 5S, 7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-2-yloxy)phenyl)- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-57 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridln-2-yloxy)phenyl)- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-58 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-4-yloxy)phenyl)- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-59 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-4-yloxy)phenyl)- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-60 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4- (aminomethyl)-1, 7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyrimidin-5-yloxy)phenyl)- 4, 5, 6,7-tetrahydro-1H-indazol-6-yl)methanol Ia-61 ((5R, 6S)-5-((1S, 3aS, 4S,5S, 7aR)-4-(aminomethyl)- 1, 7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyrimidin-5-yloxy)phenyl)- 4, 5, 6,7-tetrahydro-2H-indazol-6-yl)methanol Ia-62 (4-((5R, 6S)-5-((3aS, 4R,5S, 7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-1-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone Ia-63 (4-((5R, 6S)-5-((3aS, 4R, 5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1 H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4, 5, 6, 7-tetrahydro-2H-indazol-2-yl)phenyl)(4-(pent-4-yn- 1-yloxy)phenyl)methanone Ia-644-((5R, 6S)-5-((3aS, 4R, 5S, 7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl- 4, 5, 6,7-tetrahydro-1H-indazol-1-yl)benzoic acid Ia-65 4-((5R, 6S)-5-((3aS, 4R,5S, 7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl- 4, 5, 6,7-tetrahydro-2H-indazol-2-yl)benzoic acid

The following Synthetic Examples, which are directed to the synthesis ofthe compounds of the invention; and the following Biological Examples,which are directed to representative biological assays for the compoundsof the invention, are provided as a guide to assist in the practice ofthe invention, and are not intended as a limitation on the scope of theinvention.

Synthetic Example 1 Synthesis of((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(hydroxymethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-1)

A. Using General Procedure B with diosgenin (Compound 1, 25 g, 60.34mmol, 1 eq), imidazole (8.2 g, 120.58 mmol, 2 eq), TBSCl (9.08 g, 60.34mmol, 1 eq) and DMF (200 mL) gave the desired silyl etherYert-butyldimethyl(((4S,5′R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-5′,6a,8a,9-tetramethyl-1,3,3′,4,4′,5,5′,6,6a,6b,6′,7,8,8a,8b,9,11a,12,12a,12b-icosahydrospiro[naphtho[2′,1′:4,5]indeno[2,1-b]furan-10,2′-pyran]-4-yl)oxy)silane(Compound 2, 21 g, yield: 66%) as an off-white solid after purificationby flash column chromatography (230-400 mesh silica gel, eluted with0-15% pet ether/ethyl acetate).

B. Using General Procedure C with Compound 2 (21 g, 39.74 mmol, 1 eq),TBHP (5-6 M in decane, 36.1 mL, 198.7 mmol, 5 eq), copper(I) iodide(0.75 g, 3.97 mmol, 0.1 eq), acetonitrile (100 mL) and dichloromethane(100 mL) gave the desired enone(4S,5′R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-4-((tert-butyldimethylsilyl)oxy)-5′,6a,8a,9-tetramethyl-3′,4,4′,5,5′,6,6a,6b,6′,7,8,8a,8b,9,11a,12,12a,12b-octadecahydrospiro[naphtho[2′,1′:4,5]indeno[2,1-b]furan-10,2′-pyran]-1(3H)-one(Compound 3, 11.3 g, 53%) as an off-white solid after purification byflash column chromatography (230-400 mesh silica gel, eluted with 0-60%pet ether/ethyl acetate).

C. Using General Procedure D with Compound 3 (11.3 g, 20.83 mmol, 1 eq),1 M borane in THF solution (41.6 ml, 41.67 mmol, 2 eq), sodium perboratetetrahydrate (9.6 g, 62.51 mmol, 3 eq) and THF (110 mL) gave the desireddiol1R,2R,2aS,4S,5′R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bR)-4-((tert-butyldimethylsilyl)oxy)-5′,6a,8a,9-tetramethyldocosahydrospiro[naphtho[2′,1′:4,5]indeno[2,1-b]furan-10,2′-pyran]-1,2-diol(Compound 4, 9 g, 76%) as a white solid after purification by flashcolumn chromatography (230-400 mesh silica gel, eluted with 0-5%dichloromethane/methanol).

D. Using General Procedure H with Compound 4 (9 g, 16 mmol, 1 eq),camphorsulfonic acid (74 mg, 0.32 mmol, 0.02 eq) and2,2-dimethoxypropane (68.3 g, 656.23 mmol) gave the desired acetonidetert-butyl(((3aR,3bS,5S,5′R,7aR,7bS,9aS,9bR,10S,11R,12aS,13aS,13bR,13cR)-2,2,5′,7a,9a,10-hexamethyldocosahydrospiro[furo[3″,2″:3′,4′]cyclopenta[1′,2′:1,2]phenanthro[9,10-d][1,3]dioxole-11,2′-pyran]-5-yl)oxy)dimethylsilane(Compound 5, 9 g) as a pale brown liquid which was used as is in thenext step without any further purification.

E. Using General Procedure P with Compound 5 (9 g, 14.9 mmol, 1 eq),TBAF solution (1M in THF, 30 mL, 29.9 mmol, 2 eq) and tetrahydrofuran(90 mL) gave the desired alcohol(3aR,3bS,5S,5′R,7aR,7bS,9aS,9bR,10S,11R,12aS,13aS,13bR,13cR)-2,2,5′,7a,9a,10-hexamethyldocosahydrospiro[furo[3″,2″:3′,4′]cyclopenta[1′,2′:1,2]phenanthro[9,10-d][1,3]dioxole-11,2′-pyran]-5-ol(Compound 6, 5 g, 69% over 2 steps) as a white solid after purificationby flash column chromatography (230-400 mesh silica gel, eluted with0-30% pet ether/ethyl acetate).

F. Using General Procedure M with Compound 6 (5 g, 10.23 mmol, 1 eq),Dess-Martin periodinane (6.5 g, 15.35 mmol, 1.5 eq) and dichloromethane(50 mL) gave the desired ketone(3aR,3bS,5′R,7aR,7bS,9aS,9bR,10S,11R,12aS,13aS,13bR,13cR)-2,2,5′,7a,9a,10-hexamethylicosahydrospiro[furo[3″,2″:3′,4′]cyclopenta[1′,2′:1,2]phenanthro[9,10-d][1,3]dioxole-11,2′-pyran]-5(3aH)-one(Compound 7, 2.3 g, 46%) as a white solid after purification by flashcolumn chromatography (230-400 mesh silica gel, eluted with 0-10% petether/ethyl acetate).

G. Using General Procedure N with Compound 7 (2.3 g, 4.73 mmol), ethylformate (2.3 mL, 28.39 mmol, 6 eq) and THF (8 mL) gave the desiredketone(3aR,3bS,5′R,7aR,7bS,9aS,9bR,10S,11R,12aS,13aS,13bR,13cR)-6-(hydroxymethylene)-2,2,5′,7a,9a,10-hexamethylicosahydrospiro[furo[3″,2″:3′,4′]cyclopenta[1′,2′:1,2]phenanthro[9,10-d][1,3]dioxole-11,2′-pyran]-5(3aH)-one(Compound 8, 2.5 g) as a pale brown solid which was used as is for thenext step without any further purification.

H. Using General Procedure O with Compound 8 (2.5 g, 4.86 mmol),hydrazine hydrate (0.36 g, 7.29 mmol) and ethanol (25 mL) gave thedesired pyrazole(2R,3a′R,3b′S,5R,8a′R,8b′S,10a′S,10b′R,11′S,13a′S,14a′S,14b′R,14c′R)-2′,2′,5,8a′,10a′,11′-hexamethyl-3,3a′,3b′,4,5,5′,6,8′,8a′,8b′,9′,10′,10a′,10b′,11′,13a′,14′,14a′,14b′,14c′-icosahydro-4′H-spiro[pyran-2,12′-[1,3]dioxolo[4′,5′:3,4]furo[3″,2″:3′,4′]cyclopenta[1′,2′:5,6]naphtho[1,2-t]indazole](Compound 9, 2.3 g, 88%,over 2 steps) as a white solid afterpurification by flash column chromatography (230-400 mesh silica gel,eluted with 0-70% pet ether/ethyl acetate).

I. Using General Procedure E with Compound 9 (2.3 g, 4.50 mmol, 1 eq)and acetic acid 80% aqueous solution (15 mL) gave the desired diol(1S,2R,3aS,4aS,4bR,5R,5′R,6R,6aS,1aR,11bS,13aS,13bR)-1,5′,11a,13a-tetramethyl-3a,3′,4,4a,4b,4′,5,5′,6,6a,6′,7,8,11,11a,11b,12,13,13a,13b-icosahydro-1H-spiro[furo[3″,2″:3′,4′]cyclopenta[1′,2′:5,6]naphtho[1,2-]indazole-2,2′-pyran]-5,6-diol(Compound 10, 1.4 g, yield: 66%) as an off-white solid afterpurification by flash column chromatography (230-400 mesh silica gel,eluted with 0-3% dichloromethane/methanol).

J. Using General Procedure F with Compound 10 (1.4 g, 2.97 mmol, 1 eq),sodium metaperiodate (1.27 g, 2.95 mmol, 2 eq), THF (20 mL) and water(10 mL) gave the desired dialdehyde((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-formyl-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carbaldehyde(Compound 11, 1.2 g, 85%) as a pale yellow foam after purification byflash column chromatography (230-400 mesh silica gel, eluted with 0-1%dichloromethane/methanol).

K. Using General Procedure G with Compound 11 (1.2 g, 2.56 mmol, 1 eq),sodium borohydride (0.195 g, 5.12 mmol, 2 eq), THF (15 mL) and methanol(5 mL) gave the desired diol((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(hydroxymethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-1, 1.3 g, 41%) as a pale yellow solid after purification byflash column chromatography (230-400 mesh silica gel, eluted with 0-10%dichloromethane/methanol).

LCMS: (Method 1b) MS m/z: 473.5 (M+1), t_(R): 4.04 min, Purity: 95.02%(max), 90.75% (220 nm).

HPLC: (Method 2a) t_(R): 4.00 min, Purity: 93.75% (max), 90.25% (220nm).

¹H-NMR (400 MHz, DMSO-d⁶): δ 12.18 (bs, 1H), 7.19 (bs, 1H), 4.49-4.44(m, 1H), 4.26-4.23 (m, 2H), 3.81-3.79 (m, 1H), 3.71-3.68 (m, 1H),3.43-3.36 (m, 2H), 3.24-3.21 (m, 1H), 3.19-3.01 (m, 2H), 3.00-2.95 (m,1H), 2.09-2.07 (m, 2H), 1.86-1.75 (m, 2H), 1.66-1.51 (m, 10H), 1.36-1.33(m, 3H), 1.11-1.08 (m, 2H), 0.96-0.89 (m, 6H), 0.75-0.74 (m, 6H).

Synthetic Example 2 Synthesis of((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(aminomethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-2)

A. Using General Procedure A with((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(hydroxymethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol (Compound Ia-1, from Example 1, 0.4 g, 0.846 mmol, 1 eq), Ac₂O(0.18 g, 1.77 mmol, 2.1 eq) and pyrindine (10 mL) gave the desireddiacetate((5R,6S)-1-acetyl-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(hydroxymethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methylacetate (Compound 12, 0.250 g, 47%) as a white foam after purificationby flash column chromatography (230-400 mesh silica gel, eluted with0-4% dichloromethane/methanol).

B. Using General Procedure I with Compound 12 (0.250 g, 0.449 mmol, 1eq), triethylamine (0.13 mL, 0.0.675 mmol, 1.5 eq), MsCl (0.038 mL, 0.5mmol, 1.1 eq) and dichloromethane (12 mL) gave the desired mesylate((5R,6S)-1-acetyl-5-methyl-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-3,3b,5′-trimethyl-7-(((methylsulfonyl)oxy)methyl)tetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methylacetate (Compound 13, 0.25 g) as an colorless gum which was used as isfor the next step without any further purification.

C. Using General Procedure J with Compound 13 (0.25 g, 0.394 mmol, 1eq), sodium azide (0.256 g, 3.94 mmol, 10 eq) and DMF (5 mL) gave thedesired azide((5R,6S)-1-acetyl-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(azidomethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methylacetate (Compound 14, 0.190 g, yield: 80%) as an off-white solid afterpurification by flash column chromatography (230-400 mesh silica gel,eluted with 0-30% pet ether/ethyl acetate).

D. Using General Procedure R with Compound 14 (0.19 g, 0.337 mmol, 1eq), LAH solution (1 M in THF solution, 1.3 mL, 1.34 mmol, 3 eq) and THF(10 mL) gave the desired amine((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(aminomethyl)-3,3b,5′-trimethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-2, 36 mg, 23%) as an white solid after purification bypreparative HPLC (method 3a).

LCMS: (Method 1b) 472.5 (M+1), t_(R): 3.317 min, 99.56% (Max), 92.46%(220 nm).

HPLC: (Method 2a) t_(R): 3.146 min, 95.98% (ELSD), 94.86% (220 nm).

¹H-NMR (400 MHz, DMSO-d⁶): δ 12.24 (bs, 1H), 7.62-7.60 (m, 3H),7.41-7.25 (m, 1H), 4.50-4.47 (m, 1H), 4.29-4.27 (m, 1H), 3.70-3.68 (m,1H), 3.45-3.43 (m, 1H), 3.25-3.15 (m, 3H), 2.97-2.92 (m, 2H), 2.33-2.26(m, 2H), 2.13-2.11 (m, 1H), 1.97-1.82 (m, 3H), 1.71-1.49 (m, 8H),1.40-1.23 (m, 4H), 1.09-1.06 (m, 1H), 0.92-0.90 (m, 6H), 0.81-0.70 (m,6H).

Synthetic Example 3 Synthesis of(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-1-ol(Compound Ia-3)

A. Using General Procedure B with (2S,4aR,4bS,6aS,9aS,9bR,9cR,12aR,12bS)-2-hydroxy-4a,6a,11,11-tetramethylhexadecahydro-7H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-one(Compound 15, as prepared in U.S. Pat. No. 6,046,185, 25 g, 69.01 mmol,1 eq), imidazole (14.1 g, 207.03 mmol, 3 eq), TBSCl (10.4 g, 69.01 mmol,1 eq) and dichloromethane (300 mL) gave the desired(2S,4aR,4bS,6aS,9aS,9bR,9cR,12aR,12bS)-2-((tert-butyldimethylsilyl)oxy)-4a,6a,11,11-tetramethylhexadecahydro-7H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-one(Compound 16, 10 g, 31%) as a white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-10% petether/ethyl acetate).

B. To a solution of Compound 16 (10 g, 20.99 mmol, 1 eq) in THF (100 mL)taken in a 500 mL three-necked RB flask was added methyllithium (1.6 Min diethyl ether, 39 mL, 62.98 mmol) slowly dropwise at 0° C. Reactionmass was extern ally cooled with the help of ice bath. Reaction mass wasstirred with the help of a magnetic stirrer and the reaction was carriedout under a nitrogen atmosphere. The reaction mass was slowly warmed toroom temperature and stirred for 12 h.

Completion of the reaction was monitored by TLC analysis. The reactionmass was cooled to 0° C. quenched with saturated aqueous NaHCO₃ solution(50 mL) and extracted with ethyl acetate (2×100 mL). The organic phasewas washed with brine (2×100 mL), dried over anhydrous sodium sulphateand concentrated on a rotary evaporator at 45° C. to get a crudecolorless gum. It was further purified by column chromatography (230-400mesh silica gel, eluted with 0-40% pet ether/ethyl acetate) to afford(2S,4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-2-((tert-butyldimethylsilyl)oxy)-4a,6a,7,11,11-pentamethylhexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-ol(Compound 17, 10 g, 96%) as a white solid.

C. Using General Procedure P with Compound 17 (10 g, 20.3 mmol, 1 eq)TBAF solution (1M in THF, 40 mL, 40.6 mmol) and THF (100 mL) gave thedesired dilol(2S,4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-4a,6a,7,11,11-pentamethylhexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxole-2,7-diol(Compound 18, 6.8 g, 89%) as a white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-70% petether/ethyl acetate).

D. Using General Procedure M with Compound 18 (6.8 g, 17.9 mmol, 1 eq),Dess-Martin periodinane (11.45 g, 26.9 mmol, 1.5 eq) and dichloromethane(70 mL) gave the desired ketone(4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-7-hydroxy-4a,6a,7,11,11-pentamethylhexadecahydro-2H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-one(Compound 19, 4 g, 59%) as a white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-10% petether/ethyl acetate).

E. Using General Procedure N with Compound 19 (4 g, 10.63 mmol, 1 eq),sodium hydride (60% in paraffin oil, 1.5 g, 42.52 mmol, 4 eq),tetrahydrofuran (40 mL), and ethyl formate (5.2 mL, 63.78 mmol, 6 eq)gave the desired enone(4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-7-hydroxy-3-(hydroxymethylene)-4a,6a,7,11,11-pentamethylhexadecahydro-2H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-one(Compound 20, 4 g, 93%) as a yellow solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-15% petether/ethyl acetate).

F. Using General Procedure O with Compound 20 (4 g, 9.89 mmol, 1 eq),hydrazine hydrate (0.74 g, 14.84 mmol) and ethanol (40 mL) gave thedesired pyrazole(1S,3aS,3bR,3cR,6aR,6bS,11aR,11bS,13aS)-1,5,5,11a,13a-pentamethyl-1,2,3,3a,3b,3c,6a,6b,7,8,11,11a,11b,12,13,13a-hexadecahydrocyclopenta[5,6][1,3]dioxolo[4′,5′:3,4]naphtho[1,2-]indazol-1-ol(Compound 21, 3.7 g, 94%) as a pale yellow solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-60% petether/ethyl acetate).

G. Using General Procedure E with Compound 21 (3.7 g, 9.24 mmol, 1 eq)and acetic acid (80% aqueous, 20 mL) gave the desired triol(1S,3aS,3bR,4R,5R,5aS,10aR,10bS,12aS)-1,10a,12a-trimethyl-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f]indazole-1,4,5-triol(Compound 22, 3.2 g) as a crude brown solid which was used for the nextstep without further purification.

H. Using General Procedure F with Compound 22 (3.2 g, 8.88 mmol, 1 eq),sodium metaperiodate (3.8 g, 17.76 mmol, 2 eq), THF (32 mL) and water(16 mL) gave the desired dialdehyde(5R,6S)-5-((1S,3aS,4R,5S,7aS)-4-formyl-1-hydroxy-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carbaldehyde(Compound 23, 3 g, 93% over 2 steps) as a white solid after purificationby column chromatography (230-400 mesh silica gel, eluted with 0-1%dichloromethane/methanol).

I. Using General Procedure G with Compound 23 (3 g, 8.37 mmol, 1 eq),sodium borohydride (0.795 g, 20.9 mmol, 2.5 eq), THF (20 mL) andmethanol (10 mL) gave the desired triol(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-1-ol(Compound Ia-3, 1.3 g, 43%) as a pale yellow solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-20%dichloromethane/methanol).

LCMS: (Method 1b) MS m/z: 363.3 (M+1), t_(R): 1.96 min, Purity: 95.36%(max), 92.04% (220 nm).

HPLC: (Method 2a) t_(R):1.973 min, Purity: 94.29% (max), 91.75% (220nm).

¹H-NMR (400 MHz, DMSO-d⁶): δ 12.20 (bs, 1H), 7.24-7.17 (m, 1H),4.42-4.41 (m, 1H), 4.29-4.10 (m, 2H), 4.08-4.04 (m, 1H), 3.75-3.69 (m,2H), 3.44-3.40 (m, 1H), 3.18-3.05 (m, 2H), 3.04-2.95 (m, 1H), 2.15-2.07(m, 2H), 1.80-1.52 (m, 4H), 1.51-1.33 (m, 6H), 1.22-1.17 (m, 2H),1.15-1.13 (s, 3H), 1.00-0.93 (s, 3H), 0.75-0.72 (s, 3H).

Synthetic Example 4 Synthesis of (1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol(Compound Ia-4)

A. To a stirred solution of n-butyllithium (1.6 M in Hexane, 31.20 mL,49.92 mmol) in THF (20 mL) at −78° C. was added a solution of2-bromopyridine (9.2 g, 58.24 mmol) in THF (30 mL) dropwise. The mixturewas stirred at −78° C. for 20 minutes, then a solution of(2S,4aR,4bS,6aS,9aS,9bR,9cR,12aR,12bS)-2-((tert-butyldiphenylsilyl)oxy)-4a,6a,11,11-tetramethylhexadecahydro-7H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-one(Compound 24, as prepared in U.S. Pat. No. 9,765,085, 10 g, 16.64 mmol)in THF (50 mL) was added. The resultant solution was stirred at 0° C.for 2.5 hours. The mixture was diluted with ice cold water (1×50 mL) andthe aqueous was extracted with EtOAc (2×50 mL) and washed with brine(1×50 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (230-400 mesh, 0-30% pet ether/ethyl acetate) to afford(2S,4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-2-((tert-butyldiphenylsilyl)oxy)-4a,6a,11,11-tetramethyl-7-(pyridin-2-yl)hexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-ol(Compound 25, 8.5 g, 75%) as a yellow foam.

B. Using General Procedure P with Compound 25 (8.5 g, 12.50 mmol), TBAFsolution (1 M in THF, 25.0 mL, 25.0 mmol), and tetrahydrofuran (80 mL)gave the desired alcohol(2S,4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-4a,6a,11,11-tetramethyl-7-(pyridin-2-yl)hexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxole-2,7-diol(Compound 26, 4.0 g, 72%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-60% petether/ethyl acetate).

C. Using General Procedure L with Compound 26 (4.0 g, 9.06 mmol), NMO(2.12 g, 18.12 mmol), 4 Å molecular sieves (4.0 g) and TPAP (0.75 g,2.13 mmol) in CH₂Cl₂ (40 mL) gave the desired ketone(4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-7-hydroxy-4a,6a,11,11-tetramethyl-7-(pyridin-2-yl)hexadecahydro-2H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-one(Compound 27, 3.5 g, 88%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 15-20% petether/ethyl acetate).

D. To a stirred solution of Compound 27 (3.5 g, 7.96 mmol) in toluene(30 mL) at 0° C. were added sodium methoxide solution (25% wt. in MeOH,3.4 mL, 12.46 mmol) and ethyl formate (3.21 mL, 39.81 mmol) dropwise.The resultant solution was stirred at room temperature for 3.5 hours.The mixture was evaporated under reduced pressure and the residue wasdiluted with ice cold water (1×30 mL). The aqueous was extracted withEtOAc (2×30 mL) and washed with brine (1×10 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography on silica gel (230-400 mesh, 10-20% petether/ethyl acetate) to afford(4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-7-hydroxy-3-(hydroxymethylene)-4a,6a,11,11-tetramethyl-7-(pyridin-2-yl)hexadecahydro-2H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-one(Compound 28, 3.0 g, 81%) as a brown gummy solid.

E. Using General Procedure O with Compound 28 (3.0 g, 6.42 mmol) andhydrazine hydrate (0.63 mL, 12.83 mmol) in EtOH (30 mL) gave the desiredpyrazole(1S,3aS,3bR,3cR,6aR,6bS,11aR,11bS,13aS)-5,5,11a,13a-tetramethyl-1-(pyridin-2-yl)-1,2,3,3a,3b,3c,6a,6b,7,8,11,11a,11b,12,13,13a-hexadecahydrocyclopenta[5,6][1,3]dioxolo[4′,5′:3,4]naphtho[1,2-]indazol-1-ol(Compound 29, 2.5 g, 84%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 60-80% petether/ethyl acetate).

F. Using General Procedure E with Compound 29 (2.5 g, 5.39 mmol) in 80%AcOH (25 mL) gave the desired trialcohol(1S,3aS,3bR,4R,5R,5aS,10aR,10bS,12aS)-10a,12a-dimethyl-1-(pyridin-2-yl)-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f]indazole-1,4,5-triol(Compound 30, 2.0 g, 88%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 10-15%methanol/dichloromethane).

LCMS: (Method 1e) MS m/z: 424.1 (M+1), t_(R): 2.185 min, Purity: 92.18%(UV).

HPLC: (Method 2e) t_(R): 5.464 min, Purity: 91.32% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 8.54-8.53 (m, 1H), 7.81-7.77 (m, 1H),7.57-7.55 (m, 1H), 7.29-7.26 (m, 1H), 7.23 (s, 1H), 3.29-3.06 (m, 3H),2.55-2.25 (m, 4H), 2.09-1.95 (m, 3H), 1.70-1.40 (m, 6H), 1.10 (s, 3H),0.80 (s, 3H), 0.70-0.64 (m, 1H), 0.19-0.12 (m, 1H).

G. Using General Procedure F with Compound 30 (2.5 g, 5.90 mmol) andsodium metaperiodate (2.52 g, 11.80 mmol) in THF:water (4:1, 25 mL) gavethe desired dialdehyde(5R,6S)-5-((1S,3aS,4R,5S,7aS)-4-formyl-1-hydroxy-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-5-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carbaldehyde(Compound 31, 1.8 g, 72%) as a white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-5%methanol/dichloromethane).

H. Using General Procedure G with Compound 31 (1.8 g, 4.27 mmol) andsodium borohydride (0.32 g, 8.46 mmol) in THF:MeOH (1:1, 20 mL) gave thedesired trialcohol(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol(Compound Ia-4, 0.85 g, 47%) as a white solid after purification bycolumn chromatography (Neutral alumina, eluted with 0-5%methanol/dichloromethane).

LCMS: (Method 1e) MS m/z: 426.2 (M+1), t_(R): 2.098 min, Purity: 94.81%(UV).

HPLC: (Method 2e) t_(R): 4.563 min, Purity: 99.09% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 8.51 (d, J=4.8 Hz, 1H), 7.80-7.76 (m, 1H),7.56 (d, J=8.0 Hz, 1H), 7.29-7.23 (m, 2H), 4.02-3.99 (m, 1H), 3.79-3.62(m, 2H), 3.28-3.23 (m, 1H), 3.12-3.06 (m, 1H), 2.63-2.41 (m, 3H),2.14-2.05 (m, 4H), 1.91-1.88 (m, 1H), 1.70-1.59 (m, 2H), 1.49-1.31 (m,4H), 1.09 (s, 3H), 1.04 (s, 3H), 0.02 (bs, 1H).

Synthetic Example 5 Synthesis of((5R,6S)-5-((3aS,6S,7R,7aS)-7-(hydroxymethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-&-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-5)

A. To a stirred solution of Compound 24 (from Example 4, 5.0 g, 8.32mmol) in THF (50 mL) at 0° C. were addedN-phenyl-bis(trifluoromethanesulfonimide) (5.95 g, 16.64 mmol) andlithium bis(trimethylsilyl)amide (1 M in THF, 24.96 mL, 24.96 mmol)dropwise. The resultant solution was stirred at room temperature for 2.5hours. The mixture was diluted with ice cold water (1×50 mL) and theaqueous was extracted with EtOAc (2×50 mL) and washed with brine (1×50mL). The organic layer was dried over Na₂SO₄, filtered and concentrated.The residue was purified by column chromatography on silica gel (230-400mesh, 0-5% pet ether/ethyl acetate) to afford(2S,4aR,4bS,6aS,9aS,9bR,9cR,12aR,12bS)-2-((tert-butyldiphenylsilyl)oxy)-4a,6a,11,11-tetramethyl-2,3,4,4a,4b,5,6,6a,9,9a,9b,9c,12a,12b-tetradecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-yltrifluoromethanesulfonate (Compound 32, 5.1 g, 84%) as an off-whitesolid.

B. To a stirred solution of Compound 32 (5.1 g, 6.96 mmol) in DMF (50mL) were added phenyl boronic acid (1.02 g, 8.35 mmol) and potassiumcarbonate (1.92 g, 13.92 mmol) at room temperature. The reaction mixturewas degassed with nitrogen for 20 minutes. To the solution was addedtetrakis(triphenylphosphine)palladium(0) (0.80 g, 0.70 mmol) and thereaction was heated to 80° C. and stirred for 3 hours. The reactionmixture was filtered through the bed of CELITE® and the filtrate wasevaporated under reduced pressure. The residue was diluted with EtOAc(2×50 mL) then washed consecutively with water (1×10 mL) and brine (1×10mL). The organic layer was dried over Na₂SO₄, filtered and concentrated.The crude material was purified by column chromatography on silica gel(230-400 mesh, 0-10% pet ether/ethyl acetate) to affordtert-butyldiphenyl(((2S,4aR,4bS,6aS,9aS,9bR,9cR,12aR,12bS)-4a,6a,11,11-tetramethyl-7-phenyl-2,3,4,4a,4b,5,6,6a,9,9a,9b,9c,12a,12b-tetradecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-yl)oxy)silane(Compound 33, 3.1 g, 67%) as an off-white solid.

C. Following the General Procedure P with Compound 33 (3.0 g, 4.54 mmol)and TBAF (1 M in THF, 9.08 mL, 9.08 mmol) in THF (30 mL), gave thedesired alcohol(2S,4aR,4bS,6aS,9aS,9bR,9cR,12aR,12bS)-4a,6a,11,11-tetramethyl-7-phenyl-2,3,4,4a,4b,5,6,6a,9,9a,9b,9c,12a,12b-tetradecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-ol(Compound 34, 1.6 g, 84%) as a white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-50% petether/ethyl acetate).

D. Using General Procedure L with Compound 34 (1.6 g, 3.79 mmol), NMOhydrate (0.89 g, 6.58 mmol), 4 Å molecular sieves (1.6 g) and TPAP (0.13g, 0.38 mmol) in CH₂Cl₂ (15 mL), gave the desired ketone(4aR,4bS,6aS,9aS,9bR,9cR,12aR,12bS)-4a,6a,11,11-tetramethyl-7-phenyl-1,3,4,4a,4b,5,6,6a,9,9a,9b,9c,12a,12b-tetradecahydro-2H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-one(Compound 35, 1.5 g, 94%) as a white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-20% petether/ethyl acetate).

E. To a stirred solution of Compound 35 (1.5 g, 3.57 mmol) in toluene(15 mL) at 0° C. were added sodium methoxide solution (25% wt. in MeOH,1.54 mL, 5.64 mmol) and ethyl formate (1.44 mL, 17.85 mmol) dropwise.The resultant solution was stirred at room temperature for 3.5 hours.The mixture was evaporated under reduced pressure and the residue wasdiluted with ice cold water (1×15 mL). The aqueous was extracted withEtOAc (2×15 mL) and washed with brine (1×15 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated to give the desired ketone(4aR,4bS,6aS,9aS,9bR,9cR,12aR,12bS)-3-(hydroxymethylene)-4a,6a,11,11-tetramethyl-7-phenyl-1,3,4,4a,4b,5,6,6a,9,9a,9b,9c,12a,12b-tetradecahydro-2H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-one(Compound 36, 1.5 g, 94%) as a brown gummy solid which was taken fornext step without purification.

F. Using General Procedure O with Compound 36 (1.5 g, 3.34 mmol) andhydrazine hydrate (0.33 mL, 6.69 mmol) in EtOH (15 mL) gave the desiredpyrazole(3aS,3bR,3cR,6aR,6bS,11aR,11bS,13aS)-5,5,11a,13a-tetramethyl-1-phenyl-3,3a,3b,3c,6a,6b,7,8,11,11a,11b,12,13,13a-tetradecahydrocyclopenta[5,6][1,3]dioxolo[4′,5′:3,4]naphtho[1,2-t]indazole(Compound 37, 1.3 g, 88%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 40-50% petether/ethyl acetate).

G. Using General Procedure E with Compound 37 (1.3 g, 2.92 mmol) in 80%AcOH (10 mL) gave the desired dialcohol(3aS,3bR,4R,5R,5aS,10aR,10bS,12aS)-10a,12a-dimethyl-1-phenyl-3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[5,6]naphtho[1,2-f]indazole-4,5-diol(Compound 38, 0.8 g, 68%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-5%methanol/dichloromethane).

LCMS: (Method 1d) MS m/z: 405.2 (M+1), t_(R): 2.106 min, Purity: 93.14%(UV).

HPLC: (Method 2b) t_(R): 11.323 min, Purity: 94.81% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 7.39-7.36 (m, 2H), 7.31-7.27 (m, 3H),7.24-7.22 (m, 1H), 5.94-5.93 (m, 1H), 3.19-3.13 (m, 2H), 2.67-2.63 (m,1H), 2.53-2.31 (m, 3H), 2.20-2.05 (m, 2H), 1.86-1.58 (m, 5H), 1.57-1.31(m, 2H), 1.16-1.11 (m, 4H), 0.88 (s, 3H).

H. Using General Procedure F with

(3aS,3bR,4R,5R,5aS,10aR,10bS,12aS)-10a,12a-dimethyl-1-phenyl-3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[5,6]naphtho[1,2-f]indazole-4,5-diol (Compound 38, 0.75 g, 1.85 mmol)and sodium metaperiodate (0.79 g, 3.71 mmol) in THF:water (4:1) (10 mL)gave the desired dialdehyde(5R,6S)-5-((3aS,6S,7R,7aS)-7-formyl-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carbaldehyde(Compound 39, 0.78 g) as a white solid which was taken for next stepwithout purification.

I. Using General Procedure G with(5R,6S)-5-((3aS,6S,7R,7aS)-7-formyl-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carbaldehyde(Compound 39, 0.78 g, 1.94 mmol) and sodium borohydride (0.15 g, 3.97mmol) in THF/MeOH (1:1) (10 mL) gave the desired dialcohol((5R,6S)-5-((3aS,6S,7R,7aS)-7-(hydroxymethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-5, 0.70 g, 89%) as a white solid after purification bycolumn chromatography (Neutral alumina, eluted with 0-5%methanol/dichloromethane).

LCMS: (Method 1d) MS m/z: 407.2 (M+1), t_(R): 1.961 min, Purity: 91.23%(UV).

HPLC: (Method 2b) t_(R): 10.912 min, Purity: 95.73% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 7.38-7.36 (m, 2H), 7.30-7.24 (m, 3H),7.22-7.18 (m, 1H), 5.93-5.92 (m, 1H), 4.12-4.09 (m, 1H), 3.99-3.96 (m,1H), 3.79-3.76 (m, 1H), 3.21-3.17 (m, 1H), 2.75-2.28 (m, 5H), 2.18-1.80(m, 7H), 1.65-1.31 (m, 2H), 1.14 (s, 3H), 1.10 (s, 3H).

Synthetic Example 6 Synthesis of((5R,6S)-5-((3aS,6S,7R,7aS)-7-(aminomethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-&-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-6)

A. Using General Procedure B with Compound Ia-5 (from Example 5, 0.70 g,1.72 mmol), imidazole (0.35 g, 5.17 mmol) and TBSCl (0.39 g, 2.58 mmol)in DCM (10 mL), followed by purification by column chromatography onsilica gel (230-400 mesh, 70-80% pet ether/ethyl acetate) to afford((3aS,6S,7R,7aS)-6-((5R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl)methanol (Compound 40, 0.45 g, 50%) as a white solid.

B. Using General Procedure I with Compound 40 (0.45 g, 0.86 mmol) andMsCl (0.13 mL, 1.68 mmol) in pyrindine (5 mL) gave the desired mesylate((3aS,6S,7R,7aS)-6-((5R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl)methylmethanesulfonate (Compound 41, 0.45 g, 87%) as a yellow gummy solidwhich was taken for next step without purification.

C. Using General Procedure J with Compound 41 (0.45 g, 0.75 mmol) andsodium azide (0.10 g, 1.54 mmol) in DMF (5 mL), gave the desired azide(5R,6S)-5-((3aS,6S,7R,7aS)-7-(azidomethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazole(Compound 42, 0.25 g, 61% over 2 steps) as a white solid afterpurification by column chromatography (230-400 mesh silica gel, elutedwith 0-15% pet ether/ethyl acetate).

D. Using General Procedure P with Compound 42 (0.25 g, 0.46 mmol), TBAFsolution (1 M in THF, 0.92 mL, 0.92 mmol), and THF (5 mL) gave thedesired alcohol((5R,6S)-5-((3aS,6S,7R,7aS)-7-(azidomethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound 43, 0.16 g, 81%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-30% petether/ethyl acetate).

E. Using General Procedure Q with Compound 43 (0.16 g, 0.37 mmol),triphenylphosphine (0.19 g, 0.72 mmol), water (0.5 mL) and THF (4.5 mL)gave the desired amine((5R,6S)-5-((3aS,6S,7R,7aS)-7-(aminomethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-8-yl)methanol(Compound Ia-6, 35 mg, 23%) as a white solid after purification by flashcolumn chromatography (neutral alumina, eluted with 0-10%dichloromethane/methanol).

LCMS: (Method 1e) MS m/z: 406.2 (M+1), t_(R): 1.990 min, Purity: 79.34%(UV).

HPLC: (Method 2b) t_(R): 8.992 min, Purity: 84.96% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 7.37-7.18 (m, 6H), 5.93 (s, 1H), 3.96 (d,J=8.4 Hz, 1H), 3.50-3.31 (m, 1H), 3.19-3.09 (m, 1H), 2.99-2.95 (m, 1H),2.74-2.35 (m, 4H), 2.19-1.89 (m, 7H), 1.73-1.29 (m, 3H), 1.11-1.06 (m,6H).

Synthetic Example 6.1 Synthesis of(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol(Compound Ia-42)

Following the procedure as described in Synthetic Example 6 and makingnon-critical variations using Compound Ia-8 (from Example 8) to replaceCompound Ia-5, the title compound(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol(Compound Ia-42) was obtained.

LCMS: (Method 1c) MS m/z: 431.1 (M+1), t_(R): 1.408 min, Purity: 99.84%(ELSD).

Synthetic Example 6.2 Synthesis of(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol(Compound Ia-53)

Following the procedure as described in Synthetic Example 6 and makingnon-critical variations a) using Compound Ia-4 (from Example 4) toreplace Compound Ia-5 and b) using LiAlH in THF in place of triphenylphospine in water/THF to reduce the azide to amine, the title compound(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol(Compound Ia-53) was obtained.

LCMS: (Method 1h) MS m/z: 425 (M+1), t_(R): 1.74 min, Purity: 88.6%(UV).

Synthetic Example 7 Synthesis((5R,6S)-5-((4aS,5R,6S,8aS)-5-(aminomethyl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-7)

A. Using General Procedure B with(1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcydohexylacetate (Compound 44, prepared according to U.S. Pat. No. 7,601,874, 5.0g, 13.72 mmol,), imidazole (1.40 g, 20.58 mmol), TBSCl (2.26 g, 15.09mmol) and DMF (50 mL) gave the desired alcohol(1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexylacetate (Compound 45, 3.45 g, 53%) as a white foam after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-40% petether/ethyl acetate).

B. Using General Procedure I with Compound 45 (3.45 g, 7.21 mmol), MsCl(1.12 mL, 14.41 mmol) and pyridine (30 mL) gave the desired mesylate(1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-(((methylsulfonyl)oxy)methyl)octahydro-1H-inden-5-yl)cyclohexylacetate (Compound 46, 3.5 g, 87%) as a white solid which was used as isfor the next step without any further purification.

C. Using General Procedure J with Compound 46 (3.5 g, 6.29 mmol), sodiumazide (0.82 g, 12.58 mmol) and DMF (35 mL) gave the desired azide(1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexylacetate (Compound 47, 2.8 g, 88%) as an off-white solid which was usedas is for the next step without any further purification.

D. Using General Procedure K with Compound 47 (2.8 g, 5.56 mmol),potassium carbonate (anhydrous, 1.54 g, 11.13 mmol) and methanol (30 mL)gave the desired azide(1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexan-1-ol(Compound 48, 2.2 g, 86%) as a white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-10% petether/ethyl acetate).

E. Using General Procedure L with Compound 48 (2.2 g, 4.77 mmol),molecular sieves (4 Å, 2.2 g), NMO (1.12 g, 9.54 mmol), TPAP (0.17 g,0.47 mmol) and dichloromethane (20 mL) gave the desired ketone(3S,4R)-4-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexan-1-one(Compound 49, 1.5 g, 68%) as a white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-5% petether/ethyl acetate).

F. To a stirred solution of Compound 49 (4.0 g, 8.70 mmol) inMeOH:CH₂Cl₂ (1:4, 40 mL) at −78° C. was purged with ozone gas until thereaction solution turned blue in colour. The reaction mixture quenchedwith dimethyl sulphide (1.08 g, 17.40 mmol) and stirred at roomtemperature for 4 hours. The reaction mixture was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (230-400 mesh, 0-10% pet ether/ethyl acetate) to afford(3aS,4R,5S,7aS)-4-(azidomethyl)-5-((1R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-4-oxocyclohexyl)-7a-methyloctahydro-1H-inden-1-one(Compound 50, 2.5 g, 62%) as a yellow solid.

G. Following the General Procedure N with Compound 50 (1.5 g, 3.25mmol), NaH (60% in paraffin oil, 1.30 g, 32.48 mmol), ethyl formate(3.93 mL, 48.73 mmol) and THF (15 mL) gave the desired ketone(3aS,4R,5S,7aS)-4-(azidomethyl)-5-((1R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(hydroxymethylene)-1-methyl-4-oxocyclohexyl)-2-(hydroxymethylene)-7a-methyloctahydro-1H-inden-1-one(Compound 51, 0.7 g, 42%) as a white solid following purification bycolumn chromatography on silica gel (230-400 mesh, 0-10% pet ether/ethylacetate).

H. Using General Procedure O with Compound 51 (0.7 g, 1.35 mmol) andhydrazine hydrate (0.33 mL, 6.76 mmol) in EtOH (10 mL) gave the desiredpyrazole(4aS,5R,6S,8aS)-5-(azidomethyl)-6-((5R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazole(Compound 52, 0.5 g, 73%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 60-80% petether/ethyl acetate).

I. Following the General Procedure P with Compound 52 (0.5 g, 0.98 mmol)and TBAF (1 M in THF, 1.96 mL, 1.96 mmol) in THF (5 mL) gave the desiredalcohol((5R,6S)-5-((4aS,5R,6S,8aS)-5-(azidomethyl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound 53, 0.37 g, 96%) as a yellow foam which was used in the nextstep without purification.

J. Using General Procedure R with Compound 53 (0.37 g, 0.94 mmol) andLAH (2 M in THF, 0.94 mL, 1.87 mmol) in THF (5 mL), gave the desiredalcohol((5R,6S)-5-((4aS,5R,6S,8aS)-5-(aminomethyl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-7, 0.10 g, 29%) as an off-white solid after purification bycolumn chromatography (Neutral alumina, eluted with 0-15%dichloromethane/methanol).

LCMS: (Method 1b) MS m/z: 370.2 (M+1), t_(R): 1.317 min, Purity: 98.72%(UV).

HPLC: (Method 2a) t_(R): 1.410 min, Purity: 98.29% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 7.33-7.24 (m, 2H), 4.00 (dd, J=2.4, 10.8 Hz,1H), 3.44-3.39 (m, 1H), 3.33-3.27 (m, 1H), 3.18-3.12 (m, 1H), 2.94-2.90(m, 1H), 2.77-2.53 (m, 3H), 2.44-2.28 (m, 3H), 2.20-2.06 (m, 3H),1.96-1.81 (m, 1H), 1.78-1.63 (m, 3H), 1.12 (s, 3H), 1.06 (s, 3H).

Synthetic Example 8 Synthesis(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol(Compound Ia-8)

A. To a stirred solution of n-butyllithium (1.6 M in Hexane, 4.99 mL,7.99 mmol) in THF (10 mL) at −78° C. was added a solution of1,3-thiazole (0.68 g, 7.99 mmol) in THF (10 mL) dropwise. The mixturewas stirred at −78° C. for 20 minutes, then a solution of Compound 24(from Example 4, 4 g, 6.66 mmol) in THF (20 mL) was added. The resultantsolution was stirred at room temperature for 6 hours. The mixture wasdiluted with ice cold water (1×50 mL) and the aqueous was extracted withEtOAc (2×50 mL) and washed with brine (1×50 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography on silica gel (230-400 mesh, 0-30% petether/ethyl acetate) to afford(2S,4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-2-((tert-butydiphenylsilyl)oxy)-4a,6a,11,11-tetramethyl-7-(thiazol-2-yl)hexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-ol(Compound 54, 3.8 g, 83%) as a white foam.

B. Using General Procedure P with Compound 54 (3.8 g, 5.54 mmol), TBAFsolution (1 M in THF, 11.07 mL, 11.07 mmol), and THF (35 mL) gave thedesired alcohol(2S,4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-4a,6a,11,11-tetramethyl-7-(thiazol-2-yl)hexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxole-2,7-diol(Compound 55, 3.16 g) as a yellow gummy solid which was used in the nextstep without purification.

C. Following the General Procedure M with Compound 55 (3.16 g, 7.06mmol) and Dess-Martin periodane (5.99 g, 14.12 mmol) in DCM (30 mL) gavethe desired ketone(4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-7-hydroxy-4a,6a,11,11-tetramethyl-7-(thiazol-2-yl)hexadecahydro-2H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-one(Compound 56, 2.23 g, 71%) as a white solid after purification by columnchromatography on silica gel (230-400 mesh, 20-30% pet ether/ethylacetate).

D. Using General Procedure N with Compound 56 (2.23 g, 5.00 mmol), NaH(60% in paraffin oil, 0.80 g, 20.02 mmol), ethyl formate (2.43 mL, 30.03mmol) and THF (20 mL) gave the desired ketone(4aR,4bS,6aS,7S,9aS,9bR,9cR,12aR,12bS)-7-hydroxy-3-(hydroxymethylene)-4a,6a,11,11-tetramethyl-7-(thiazol-2-yl)hexadecahydro-2H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-one(Compound 57, 2.28 g, 96%) as a white solid after purification by columnchromatography on silica gel (230-400 mesh, 20-30% pet ether/ethylacetate).

E. Using General Procedure O with Compound 57 (2.28 g, 4.81 mmol) andhydrazine hydrate (0.94 mL, 19.26 mmol) in EtOH (20 mL) gave the desiredpyrazole(1S,3aS,3bR,3cR,6aR,6bS,11aR,11bS,13aS)-5,5,11a,13a-tetramethyl-1-(thiazol-2-yl)-1,2,3,3a,3b,3c,6a,6b,7,8,11,11a,11b,12,13,13a-hexadecahydrocyclopenta[5,6][1,3]dioxolo[4′,5′:3,4]naphtho[1,2-]indazol-1-ol(Compound 58, 2.16 g, 96%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 50-60% petether/ethyl acetate).

F. Using General Procedure E with Compound 58 (2.16 g, 4.60 mmol) in 80%AcOH (20 mL) gave the desired trialcohol(1S,3aS,3bR,4R,5R,5aS,10aR,10bS,12aS)-10a,12a-dimethyl-1-(thiazol-2-yl)-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-t]indazole-1,4,5-triol(Compound 59, 1.3 g, 66%) as an off-white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-10%dichloromethane/methanol).

LCMS: (Method 1d) MS m/z: 430.2 (M+1), t_(R): 1.242 min, Purity: 95.91%(UV).

HPLC: (Method 2b) t_(R): 6.987 min, Purity: 95.07% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 7.72 (d, J=3.2 Hz, 1H), 7.47 (d, J=3.2 Hz,1H), 7.24 (s, 1H), 3.29-3.09 (m, 3H), 2.58-2.26 (m, 4H), 2.13-1.91 (m,5H), 1.67-1.43 (m, 5H), 1.06 (s, 3H), 0.77 (s, 3H), 0.40-0.39 (m, 1H).

G. Using General Procedure F with Compound 59 (1.30 g, 3.03 mmol) andsodium metaperiodate (1.29 g, 6.05 mmol) in THF:water (4:1, 10 mL) gavethe desired dialdehyde(5R,6S)-5-((1S,3aS,4R,5S,7aS)-4-formyl-1-hydroxy-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-5-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carbaldehyde(Compound 60, 1.2 g, 93%) as a white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-5%dichloromethane/methanol).

H. Using General Procedure G with Compound 60 (1.20 g, 2.81 mmol) andsodium borohydride (0.21 g, 5.61 mmol) in THF:MeOH (1:1, 20 mL) gave thedesired trialcohol(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol(Compound Ia-8, 0.5 g, 41%) as a white solid after purification bycolumn chromatography (Neutral alumina, eluted with 10-15%dichloromethane/methanol).

LCMS: (Method 1d) MS m/z: 432.2 (M+1), t_(R): 1.268 min, Purity: 99.98%(ELSD).

HPLC: (Method 2a) t_(R): 2.264 min, Purity: 97.10% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 7.73 (d, J=3.2 Hz, 1H), 7.48 (d, J=3.2 Hz,11H), 7.25 (s, 11H), 4.09-4.01 (in, 11H), 3.98-3.72 (m, 2H), 3.30-3.27(m, 1H), 3.15-3.09 (m, 1H), 2.65-2.43 (i, 3H), 2.27-2.03 (m, 5H),1.68-1.40 (i, 6H), 1.06 (2×s, 6H), 0.26-0.21 (i, 1H).

Synthetic Example 9 Synthesis of(2S,5R)-5-ethyl-2-((1R,3aS,4S,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-yl)-&-methylheptan-3-ol(Compound Ia-9)

Synthetic Example 9 Continued

A. Using General Procedure B with stigmasterol (Compound 61, 30.0 g,72.75 mmol), imidazole (12.37 g, 181.73 mmol) and TBSCl (16.43 g, 109.04mmol) in DMF (300 mL) followed by purification by column chromatographyon silica gel (230-400 mesh, 0-5% pet ether/ethyl acetate) affordedter-butyl(((3S,8S,9S,10R,13R,14S,17R)-17-((2R,5S,E)-5-ethyl-6-methylhept-3-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)dimethylsilane(Compound 62, 38.0 g, 99%) as a colourless gummy solid.

B. Using General Procedure C with Compound 62 (38.0 g, 72.11 mmol), TBHP(5 M in decane, 75.0 mL, 374.97 mmol), 4 Å molecular sieves (38.0 g) andmanganese(III) acetate dihydrate (1.93 g, 7.21 mmol) in CH₂Cl₂:ACN:EtOAc(2:1:1, 380 mL), gave the desired ketone(3S,8S,9S,10R,13R,14S,17R)-3-((tert-butyldimethylsilyl)oxy)-17-((2R,5S,E)-5-ethyl-6-methylhept-3-en-2-yl)-10,13-dimethyl-1,2,3,4,8,9,10,11,12,13,14,15,16,17-tetradecahydro-7H-cyclopenta[a]phenanthren-7-one(Compound 63, 22.5 g, 58%) as an off-white solid after purification bycolumn chromatography on silica gel (230-400 mesh, 0-5% pet ether/ethylacetate).

C. Using General Procedure D with Compound 63 (22.5 g, 41.59 mmol),Borane in THF (1 M, 92.75 mL, 92.75 mmol) and sodium perboratetetrahydrate (19.20 g, 124.78 mmol) in THF (200 mL) gave the desireddialcohol(3S,5S,6R,7R,8S,9S,10R,13R,14S,17R)-3-((tert-butydimethylsilyl)oxy)-17-((2S,5R)-5-ethyl-3-hydroxy-6-methylheptan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-6,7-diol(Compound 64, 24.0 g) as a white solid which was used in the next stepwithout purification.

D. Using General Procedure H with Compound 64 (24.0 g, 41.45 mmol) andcamphorsulfonic acid (0.96 g, 4.15 mmol) in 2,2-dimethoxypropane (203mL, 1658.06 mmol) followed by purification by column chromatography onsilica gel (230-400 mesh, 10-15% pet ether/ethyl acetate) afforded(2S,5R)-2-((2S,4aR,4bS,6aR,7R,9aS,9bS,9cR,12aR,12bS)-2-((tert-butyldimethylsilyl)oxy)-4a,6a,11,11-tetramethylhexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-yl)-5-ethyl-6-methylheptan-3-ol(Compound 65, 12.0 g, 47%) as a white solid.

E. Using General Procedure A with Compound 65 (12.0 g, 19.38 mmol), DMAP(0.24 g, 1.94 mmol) and Ac₂O (5.42 mL, 57.34 mmol) in pyidine (100 mL)gave the desired ester(2S,5R)-2-((2S,4aR,4bS,6aR,7R,9aS,9bS,9cR,12aR,12bS)-2-((tert-butyldimethylsilyl)oxy)-4a,6a,11,11-tetramethylhexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-yl)-5-ethyl-6-methylheptan-3-ylacetate (Compound 66, 11.0 g, 86%) as a yellow gummy solid which wasused in the next step without purification.

F. Following the General Procedure P with Compound 66 (11.0 g, 16.64mmol) and TBAF (1 M in THF, 33.28 mL, 33.28 mmol) in THF (100 mL), gavethe desired alcohol(2S,5R)-5-ethyl-2-((2S,4aR,4bS,6aR,7R,9aS,9bS,9cR,12aR,12bS)-2-hydroxy-4a,6a,11,11-tetramethylhexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-yl)-6-methylheptan-3-ylacetate as a white solid (Compound 67, 5.0 g, 55%) after purification bycolumn chromatography on silica gel (230-400 mesh, 40-45% petether/ethyl acetate).

G. Using General Procedure L with Compound 67 (5.0 g, 9.14 mmol NMOhydrate (2.14 g, 18.29 mmol), 4 Å molecular sieves (5.0 g) and TPAP(0.32 g, 0.914 mmol) in CH₂Cl₂ (50 mL) gave the desired ketone(2S,5R)-5-ethyl-6-methyl-2-((4aR,4bS,6aR,7R,9aS,9bS,9cR,12aR,12bS)-4a,6a,11,11-tetramethyl-2-oxohexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-yl)heptan-3-ylacetate (Compound 68, 3.8 g, 76%) as an off-white solid afterpurification by column chromatography on silica gel (230-400 mesh, 5-10%pet ether/ethyl acetate).

H. Using General Procedure N with Compound 68 (3.8 g, 6.97 mmol), sodiumhydride (60% in paraffin oil, 1.39 g, 34.87 mmol) and ethyl formate(3.94 mL, 48.82 mmol) in THF (40 mL) gave the desired ketone(4aR,4bS,6aR,7R,9aS,9bS,9cR,12aR,12bS)-7-((2S,5R)-5-ethyl-3-hydroxy-6-methylheptan-2-yl)-3-(hydroxymethylene)-4a,6a,11,11-tetramethylhexadecahydro-2H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-one(Compound 69, 3.0 g, 81%) as a brown gummy solid which was used in thenext step without purification.

I. Using General Procedure O with Compound 69 (3.0 g, 5.65 mmol) andhydrazine hydrate (0.55 mL, 11.30 mmol) in EtOH (30 mL) gave the desiredpyrazole(2S,5R)-5-ethyl-6-methyl-2-((1R,3aS,3bS,3cR,6aR,6bS,11aR,11bS,13aR)-5,5,11a,13a-tetramethyl-1,2,3,3a,3b,3c,6a,6b,7,8,11,11a,11n,12,13,13a-hexadecahydrocyclopenta[5,6][1,3]dioxolo[4′,5′:3,4]naphtho[1,2-f]indazol-1-yl)heptan-3-ol(Compound 70, 1.1 g, 37%) as an off-white solid after purification bycolumn chromatography on silica gel (230-400 mesh, 40-50% petether/ethyl acetate).

J. Using General Procedure E with Compound 70 (1.1 g, 2.09 mmol) in 80%AcOH (10 mL) gave the desired dialcohol(1R,3aS,3bS,4R,5R,5aS,10aR,10bS,12aR)-1-((2S,5R)-5-ethyl-3-hydroxy-6-methylheptan-2-yl)-10a,12a-dimethyl-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-]indazole-4,5-diol(Compound 71, 0.9 g, 89%) as an off-white solid after purification bycolumn chromatography on silica gel (230-400 mesh, 10-15%methanol/dichloromethane).

K. Using General Procedure F with Compound 71 (0.9 g, 1.85 mmol) andsodium metaperiodate (0.79 g, 3.70 mmol) in THF:water (4:1, 10 mL) gavethe desired dialdehyde(5R,6S)-5-((1R,3aS,4S,5S,7aR)-1-((2S,5R)-5-ethyl-3-hydroxy-6-methylheptan-2-yl)-4-formyl-7a-methyloctahydro-1H-inden-5-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carbaldehyde(Compound 72, 0.72 g, 80%) as a white solid after purification by columnchromatography on silica gel (230-400 mesh, 0-5%methanol/dichloromethane).

L. Using General Procedure G with Compound 72 (0.72 g, 1.49 mmol) andsodium borohydride (0.11 g, 2.91 mmol) in THF:MeOH (1:1.10 mL) gave thedesired trialcohol(2S,5R)-5-ethyl-2-((1R,3aS,4S,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-yl)-6-methylheptan-3-ol(Compound Ia-9, 53 mg, 7%) as a white solid after purification bypreparative HPLC (3a).

LCMS: (Method 1d) MS m/z: 489.3 (M+1), t_(R): 2.030 min, Purity: 93.64%(UV).

HPLC: (Method 2a) t_(R): 4.10 min, Purity: 95.37% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 7.27 (s, 1H), 4.04-3.93 (m, 2H), 3.69-3.64(m, 2H), 3.35-3.33 (m, 1H), 3.23-3.22 (m, 1H), 2.69-2.65 (m, 2H),2.36-1.98 (m, 3H), 1.84-1.50 (m, 8H), 1.49-1.24 (m, 9H), 1.19-1.04 (m,4H), 0.94-0.90 (m, 9H), 0.78 (m, 6H).

Synthetic Example 10 Synthesis of(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol(Compound Ia-10a) and(1R,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol(Compound Ia-10b)

A. To a stirred solution of((3aS,4R,5S,7aS)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanol(Compound 73, as prepared in U.S. Pat. No. 9,765,085, 0.25 g, 0.72 mmol)in water/t-BuOH (1:2, 10 mL) were added sodium bicarbonate (0.91 g,10.88 mmol) and sodium metaperiodate (1.54 g, 7.26 mmol) at roomtemperature. The reaction mixture was cooled to 0° C. and added osmiumtetroxide (2.5% in t-BuOH, 73.83 mL, 7.26 mmol) dropwise. The resultantsolution was stirred at room temperature for 24 hours. The reaction wasquenched with sodium thiosulphate solution (5 g dissolved in 10 mLwater) and stirred for 20 minutes. The organic layer was extracted withethyl acetate (2×20 mL) and washed consecutively with water (1×10 mL)and brine (1×10 mL). It was dried over sodium sulphate and concentratedto give the desired dialcohol(3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-one(Compound 74, 0.20 g, 80%) as an off white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-5%dichloromethane/methanol).

B. Using General Procedure G with Compound 74 (0.25 g, 0.722 mmol, 1eq), sodium borohydride (0.054 g, 1.44 mmol, 2 eq), THF (10 mL) andmethanol (5 mL) and gave a mixture of the triols(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol(Compound Ia-10a) and(1R,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol(Compound Ia-10b) as a white solid (0.125 g, 49%) after purification byflash column chromatography (230-400 mesh silica gel, eluted with 0-20%dichloromethane/methanol).

LCMS: (Method 1b) MS m/z: 349.2 (M+1), t_(R): 2.05 min, Purity:(25.41+73.71) % (ELSD), (30.68+64.61) % (220 nm), isomeric massesobserved.

HPLC: (Method 2a) t_(R): 1.94/2.04 min, Purity: (56.86+42.66) % (ELSD),(58.68+41.05) % (220 nm).

¹H-NMR (400 MHz, DMSO-d): δ 12.17 (s, 1H), 7.17-7.13 (m, 1H), 4.42-4.41(m, 2H), 4.17-4.07 (m, 2H), 3.78-3.77 (m, 2H), 3.44-3.42 (m, 2H),3.18-3.10 (m, 3H), 2.96-2.92 (m, 1H), 2.51-2.45 (m, 2H), 2.19-2.05 (m,3H), 1.80-1.72 (m, 1H), 1.64-1.60 (m, 2H), 1.50-1.48 (m, 2H), 1.42-1.18(m, 5H), 0.96-0.93 (s, 3H), 0.82-0.78 (m, 1H), 0.63 (s, 3H).

Synthetic Example 11 Synthesis of((4aS,5R,6S,8aS)-6-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-5-yl)methanol (Compound Ia-11)

A. Using General Procedure B with Compound 44 (from Example 7, 10.0 g,27.43 mmol), imidazole (7.47 g, 109.73 mmol), TBSCl (12.40 g, 82.29mmol) and DMF (100 mL) gave the desired silyl ether (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexylacetate (Compound 75, 13.0 g, 80%) as a white solid after purificationby column chromatography on silica gel (60-120 mesh, 5-10% petether/ethyl acetate).

B. Using General Procedure K with Compound 75 (13.0 g, 21.94 mmol),potassium carbonate (6.06 g, 43.84 mmol) and MeOH (130 mL) gave thedesired alcohol(1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexan-1-ol(Compound 76, 11.0 g, 91%) as a white solid after purification by columnchromatography on silica gel (60-120 mesh, 10-20% pet ether/ethylacetate).

C. Using General Procedure L with Compound 76 (11.0 g, 19.96 mmol), NMOhydrate (5.40 g, 39.93 mmol), 4 Å molecular sieves (11.0 g), TPAP (0.70g, 1.97 mmol) and CH₂Cl₂ (100 mL) gave the desired ketone(3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexan-1-one(Compound 77, 9.0 g, 82%) as an off white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 10-15% petether/ethyl acetate).

D. To a stirred solution of Compound 77 (8.0 g, 14.59 mmol) inmethanol:dichloromethane (1:4, 80 mL) at −78° C. was bubbled ozone gasuntil the reaction solution turned blue in colour. The reaction mixturewas quenched with dimethyl sulphide (1.81 g, 29.14 mmol) and stirred atroom temperature for 4 hours. The resultant solution was concentratedunder reduced pressure to give the desired ketone(3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-((1R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-4-oxocyclohexyl)-7a-methyloctahydro-1H-inden-1-one(Compound 78, 3.0 g, 37%) as a yellow solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 10-15% petether/ethyl acetate).

E. Following the General Procedure N with Compound 78 (1.5 g, 2.72mmol), (60% in paraffin oil, 1.09 g, 27.22 mmol), ethyl formate (3.30mL, 40.83 mmol) and THF (15 mL) gave the desired ketone(3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-((1R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(hydroxymethylene)-1-methyl-4-oxocyclohexyl)-2-(hydroxymethylene)-7a-methyloctahydro-1H-inden-1-one(Compound 79, 0.6 g, 36%) as a pale yellow solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 10-15% petether/ethyl acetate).

F. Following the General Procedure O with Compound 79 (0.6 g, 0.99mmol), hydrazine hydrate (0.24 mL, 4.94 mmol) and THF (5 mL) gave thedesired pyrazole(4aS,5R,6S,8aS)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-((5R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazole(Compound 80, 0.3 g, 51%) as an off white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 30-40% petether/ethyl acetate).

G. Following the General Procedure P with Compound 80 (0.3 g, 0.50mmol), TBAF (1M in THF, 1.0 mL, 1.0 mmol) and THF (5 mL), gave thedesired alcohol((4aS,5R,6S,8aS)-6-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-5-yl)methanol(Compound Ia-11, 28 mg, 15%) as an off white solid after purification bypreparative HPLC (Method 3a).

LCMS: (Method 1d) MS m/z: 371.2 (M+1), t_(R): 1.194 min, Purity: 99.58%(UV).

HPLC: (Method 2b) t_(R): 6.097 min, Purity: 99.44% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 7.29 (s, 1H), 7.21 (s, 1H), 4.13-4.10 (m,1H), 3.99-3.96 (m, 1H), 3.80-3.77 (m, 1H), 3.40-3.37 (m, 1H), 3.23-3.14(m, 2H), 2.81-2.67 (m, 3H), 2.36-2.10 (m, 4H), 1.98-1.84 (m, 3H),1.71-1.51 (m, 2H), 1.15 (s, 3H), 1.03 (s, 3H).

Synthetic Example 12 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-12) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-13)

A. Using General Procedure N with Compound 49 (from Example 7, 1.5 g,3.27 mmol), NaH (60% in paraffin oil, 0.52 g, 13.06 mmol), ethyl formate(1.6 mL, 19.59 mmol) and THF (15 mL) gave the desired ketone(4R,5S)-4-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(hydroxymethylene)-4-methylcyclohexan-1-one(Compound 81, 1.4 g, 88%) as a pale brown solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-5% petether/ethyl acetate).

B. Using General Procedure O with Compound 81 (1 g, 2.06 mmol, 1 eq),4-fluorophenylhydrazine (0.5 g, 3.07 mmol, 1.5 eq) and ethanol (20 mL)gave a mixture of pyrazoles(5R,6S)-5-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazole(Compound 82a, 0.5 g, 42%) and(5R,6S)-5-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazole(Compound 82b) as a pale brown gum after purification by flash columnchromatography (230-400 mesh silica gel, eluted with 0-30% petether/ethyl acetate).

C. Using General Procedure P with the mixture of Compound 82a andCompound 82b (0.5 g, 0.87 mmol, 1 eq), TBAF solution (1M in THF, 1.7 mL,1.73 mmol, 2 eq) and THF (15 mL) gave the desired alcohols(((5R,6S)-5-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound 83a, 0.26 g, 65%) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound 83b) as a pale yellow solids after purification by flashcolumn chromatography (230-400 mesh silica gel, eluted with 0-40% petether/ethyl acetate).

D. Using General Procedure Q with Compound 83a (0.260 g, 0.561 mmol, 1eq), triphenylphosphine (0.294 g, 1.12 mmol, 2 eq) water (1 mL) and THF(15 mL) gave the desired amine((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-12, 55 mg, 22%) as an off-white solid after purification bypreparative HPLC (method 3b).

LCMS: (Method 1b) MS m/z: 438.3 (M+1), t_(R): 3.923 min, Purity: 98.07%(ELSD), 93.9% (220 nm).

HPLC: (Method 2b) t_(R): 3.914 min, 96.55% (ELSD), 91.9% (220 nm).

¹H-NMR (400 MHz, MeOD): δ 7.59-7.54 (m, 2H), 7.49-7.45 (m, 1H),7.30-7.24 (m, 2H), 4.67-4.63 (m, 2H), 3.97-3.93 (m, 1H), 3.44-3.41 (m,1H), 3.11-3.07 (m, 1H), 2.97-2.94 (m, 1H), 2.78-2.74 (m, 1H), 2.67-2.50(m, 2H), 2.48-2.44 (m, 1H), 2.15-2.14 (m, 2H), 1.94-1.82 (m, 4H),1.68-1.60 (m, 3H), 1.46-1.44 (m, 2H), 1.31-1.25 (m, 2H), 1.14-1.00 (s,3H), 0.90-0.82 (s, 3H).

E. Using General Procedure Q with Compound 83b (0.260 g, 0.561 mmol, 1eq), triphenylphosphine (0.294 g, 1.12 mmol, 2 eq) water (1 mL) and THF(15 mL) gave the desired amine((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-13).

LCMS: (Method 1b) MS m/z: 438.2 (M+1), t_(R): 2.502 min, Purity: 94.40%(UV).

Synthetic Example 12.1 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-14) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-15)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using 4-methoxyphenyl hydrazine to replace4-fluorophenyl hydrazine in the conversion of Compound 81 to the mixtureof Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-14) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-15) were obtained.

Compound Ia-14: LCMS: (Method 1c) MS m/z: 450.3 (M+1), t_(R): 1.949 min,Purity: 94.29% (UV).

Compound Ia-15: LCMS: (Method 1d) MS m/z: 450.3 (M+1), t_(R): 1.566 min,Purity: 99.49% (UV).

Synthetic Example 12.2 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-16) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-17)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using (4-methoxybenzyl)hydrazine to replace4-fluorophenyl hydrazine in the conversion of Compound 81 to the mixtureof Compounds 82a and 82b, the title compounds of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-8-yl)methanol(Compound Ia-16) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-17) were obtained.

Compound Ia-17: LCMS: (Method 1c) MS m/z: 464.3 (M+1), t_(R): 2.322 min,Purity: 98.70% (UV).

Synthetic Example 12.3 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-18) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-19)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using (4-fluorobenzyl)hydrazine to replace4-fluorophenyl hydrazine in the conversion of Compound 81 to the mixtureof Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-18) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-19) were obtained.

Compound Ia-19: LCMS: (Method 1c) MS m/z: 452.3 (M+1), t_(R): 2.386 min,Purity: 99.29% (UV).

Synthetic Example 12.4 Synthesis of4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone(Compound Ia-20) and(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone(Compound Ia-21)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using (4-hydrazineylphenyl)(phenyl)methanone toreplace 4-fluorophenyl hydrazine in the conversion of Compound 81 to themixture of Compounds 82a and 82b, the title compounds4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone(Compound Ia-20) and(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone(Compound Ia-21) were obtained.

Compound Ia-20: LCMS: (Method 1d) MS m/z: 524.3 (M+1), t_(R): 1.678 min,Purity: 98.70% (UV).

Synthetic Example 12.5 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-22) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-23)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using (3,4-difluorophenyl)hydrazine to replace4-fluorophenyl hydrazine in the conversion of Compound 81 to the mixtureof Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-22) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-23) were obtained.

Compound Ia-22: LCMS: (Method 1d) MS m/z: 456.2 (M+1), t_(R): 2.014 min,Purity: 99.42% (UV).

Compound Ia-23: LCMS: (Method 1d) MS m/z: 456.3 (M+1), t_(R): 1.547 min,Purity: 97.38% (UV).

Synthetic Example 12.6 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-24) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-25)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using (4-(4-fluorophenoxy)phenyl)hydrazine toreplace 4-fluorophenyl hydrazine in the conversion of Compound 81 to themixture of Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-24) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-25) were obtained.

Compound Ia-24: LCMS: (Method 1c) MS m/z: 530.2 (M+1), t_(R): 0.995 min,Purity: 97.05% (UV).

Compound Ia-25: LCMS: (Method 1d) MS m/z: 530.3 (M+1), t_(R): 1.801 min,Purity: 98.10% (UV).

Synthetic Example 12.7 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-26) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-27)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using 5-fluoro-2-hydrazineylpyrimidine toreplace 4-fluorophenyl hydrazine in the conversion of Compound 81 to themixture of Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-26) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-27) were obtained.

Compound Ia-26: LCMS: (Method 1c) MS m/z: 440.2 (M+1), t_(R): 2.126 min,Purity: 96.50% (UV).

Compound Ia-27: LCMS: (Method 1c) MS m/z: 440.2 (M+1), t_(R): 2.237 min,Purity: 95.86% (UV).

Synthetic Example 12.8 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-1-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-28) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-29)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using (4-phenoxyphenyl)hydrazine to replace4-fluorophenyl hydrazine in the conversion of Compound 81 to the mixtureof Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-1-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-28) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-29) were obtained.

Compound Ia-28: LCMS: (Method 1c) MS m/z: 512.3 (M+1), t_(R): 2.706 min,Purity: 91.51% (UV).

Compound Ia-29: LCMS: (Method 1d) MS m/z: 512.3 (M+1), t_(R): 2.056 min,Purity: 94.40% (UV).

Synthetic Example 12.9 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-30) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-31)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using 5-fluoro-2-hydrazineylpyridine to replace4-fluorophenyl hydrazine in the conversion of Compound 81 to the mixtureof Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-30) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-31) were obtained.

Compound Ia-30: LCMS: (Method 1c) MS m/z: 439.2 (M+1), t_(R): 2.494 min,Purity: 99.71% (UV).

Synthetic Example 12.10 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-32) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-33)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using 2-fluorophenyl hydrazine to replace4-fluorophenyl hydrazine in the conversion of Compound 81 to the mixtureof Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-32) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-33) were obtained.

Compound Ia-32: LCMS: (Method 1c) MS m/z: 438.3 (M+1), t_(R): 1.503 min,Purity: 89.45% (UV).

Synthetic Example 12.11 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-34) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-35)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using 2,4-difluorophenyl hydrazine to replace4-fluorophenyl hydrazine in the conversion of Compound 81 to the mixtureof Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-34) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-35) were obtained.

Compound Ia-34: LCMS: (Method 1d) MS m/z: 456.2 (M+1), t_(R): 1.443 min,Purity: 99.10% (ELSD).

Synthetic Example 12.12 Synthesis of4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenoxy)benzoicacid (Compound Ia-36) and4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenoxy)benzoicacid (Compound Ia-37)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using methyl 4-(4-hydrazineylphenoxy)benzoate toreplace 4-fluorophenyl hydrazine in the conversion of Compound 81 to themixture of Compounds 82a and 82b, the title compounds4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenoxy)benzoicacid (Compound Ia-36) and4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenoxy)benzoicacid (Compound Ia-37) were obtained after hydrolysis of the ester withLiOH in THF:MeOH:water (7:2:1) at 65° C. for 2 hours.

Compound Ia-36: LCMS: (Method 1c) MS m/z: 556.3 (M+1), t_(R): 2.552 min,Purity: 99.977% (ELSD).

Synthetic Example 12.13 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-38) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-39)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using (4,4-difluorocyclohexyl)hydrazine toreplace 4-fluorophenyl hydrazine in the conversion of Compound 81 to themixture of Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-38) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-39) were obtained.

Compound Ia-39: LCMS: (Method 1c) MS m/z: 462.3 (M+1), t_(R): 2.295 min,Purity: 97.32% (UV).

Synthetic Example 12.14 Synthesis of((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-40) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-41)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using 3-fluorophenyl hydrazine to replace4-fluorophenyl hydrazine in the conversion of Compound 81 to the mixtureof Compounds 82a and 82b, the title compounds((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-40) and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-41) were obtained.

Compound Ia-40: LCMS: (Method 1d) MS m/z: 438.3 (M+1), t_(R): 1.524 min,Purity: 93.14% (UV).

Synthetic Example 12.15 Synthesis of(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone(Compound Ia-62) and(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone(Compound Ia-63)

A. To a solution of 4-nitrobenzoyl chloride (4.25 g, 23.1 mmol) in DCM(50 mL) was added anisole (5.0 g, 46.3 mmol) and AlCl₃ (3.08 g, 23.1mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h then atRT for 12 h under N₂. Reaction completion was checked by TLC. Thereaction mixture was quenched with ice, extracted with DCM (50 mL), andwashed with brine (2×25 mL). The organic layer was separated and driedover Na₂SO₄ then concentrated to dryness. The crude product was purifiedby column chromatography (230-400 mesh silica gel, eluted with 40-50%pet ether/EtOAc) to give (4-methoxyphenyl)(4-nitrophenyl)methanone (6.50g, 54%) as a colourless solid. LCMS: (Method 1d) MS m/z: 258 (M+1),t_(R): 2.36 min, Purity: 75.3% (UV).

B. To a solution of (4-methoxyphenyl)(4-nitrophenyl)methanone (6.50 g,26.8 mmol) in glacial AcOH (20 mL) was added HBr in AcOH (33%, 33.0 mL,134 mmol). The reaction mixture was refluxed for 16 h under N₂. Reactioncompletion was checked by LCMS. The reaction mixture was cooled to RT,quenched with ice water (50 mL) and concentrated by rotary evaporator toremove AcOH. The residue obtained was diluted with EtOAc (50 mL), washedwith brine (2×25 mL). The organic layer was dried over Na₂SO₄ andconcentrated to dryness. The crude product was purified by columnchromatography (230-400 mesh silica gel, eluted with 40-50% pet.ether/EtOAc) to give (4-hydroxyphenyl)(4-nitrophenyl)methanone (5.70 g,93%) as a colorless solid. LCMS: (Method 1d) MS m/z: 243 (M+1), t_(R):1.93 min, Purity: 74.6% (UV).

C. To a solution of triphenylphosphine (9.26 g, 35.3 mmol) in THF (45mL) was added DIAD (7.00 mL, 35.3 mmol) at 0° C. Stirring was continuedfor 30 min after which pent-4-yn-1-ol (3.20 mL, 35.3 mmol) was added at0° C. Reaction was stirred for a further 30 min, after which(4-hydroxyphenyl)(4-nitrophenyl)methanone (5.70 g, 23.5 mmol) in THF (5mL) was added dropwise. The reaction mixture was stirred for 3 h underN₂. Reaction completion was checked by TLC. The reaction mixture wasdiluted with EtOAc (50 mL), washed with brine (2×25 mL). The organiclayer was dried over Na₂SO₄ and concentrated to dryness. The crudeproduct purified by column chromatography (230-400 mesh silica gel,eluted with 30-40% pet. ether/EtOAc) to give(4-nitrophenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone (3.80 g, 53%) asan off white solid. LCMS: (Method 1f) MS m/z: 310 (M+1), t_(R): 2.75min, Purity: 89.1% (UV).

D. To a solution of(4-nitrophenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone (3.80 g, 12.3mmol,) in EtOH (40 mL) and water (5 mL) was added NH₄Cl (3.20 g, 61.4mmol). The reaction mixture was heated at 80° C. under N₂. At thistemperature, Fe metal powder (3.43 g, 61.4 mmol) was added and stirringwas continued for 4 h. The reaction mixture was cooled to RT, filteredthrough CELITE™ bed and concentrated to dryness. The crude product waspurified by column chromatography (230-400 mesh silica gel, eluted with40-50% pet. ether/EtOAc) to get the desired(4-aminophenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone (2.20 g, 64%) as apale, yellow solid. LCMS: (Method 1k), MS m/z: 280 (M+1), t_(R): 2.75min, Purity: 83.5% (UV).

E. To a cold aqueous solution of HCl (12 N, 5.2 mL) was added(4-nitrophenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone (1.30 g, 4.6mmol). An ice-cold solution of NaNO₂ (0.26 g, 3.8 mmol) in water (4.5mL) was added dropwise to the reaction mass and stirred for 20 min at 0°C. SnCl₂ (2.3 g, 12.2 mmol) in HCl (12 N, 8.8 mL) was added dropwise tothe reaction flask and stirring was continued for 4 h at RT. Theprecipitate formed was filtered, washed with HCl (1 N) to give(4-hydrazineylphenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone, hydrogenchloride salt (1.20 g, 86%) as a yellow solid, which was taken to nextstep without any further purification. LCMS: (Method 1) MS m/z: 295(M+1), t_(R): 1.76 min, Purity: 76.7% (UV).

F. Following the procedure as described in Synthetic Example 12 andmaking non-critical variations using(4-hydrazineylphenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanonehydrochloride (prepared above) to replace phenyl hydrazine, the titlecompounds,(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone(Compound Ia-62) and(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone(Compound Ia-63), were obtained after purification by preparative HPLC(Method 3c).

Compound Ia-62: LCMS: (Method 1k) MS m/z: 606 (M+1), t_(R): 3.17 min,Purity: 99.21% (UV).

HPLC: (Method 2d) t_(R) ^(: 11.65) min, Purity: 98.8% (UV).

1H-NMR (400 MHz, CD₃OD): δ 7.91-7.88 (m, 4H), 7.86-7.82 (m, 2H), 7.57(s, 1H), 7.10-7.07 (m, 2H), 4.69 (s, 2H), 4.20 (t, J=6.0 Hz, 2H), 3.94(dd, J=10.8, 2.4 Hz, 1H), 3.50-3.31 (m, 2H), 3.25-3.12 (m, 2H),2.80-2.76 (m, 2H), 2.51-2.37 (m, 5H), 2.28-2.27 (m, 1H), 2.05-1.88 (m,6H), 1.70-1.29 (m, 6H), 1.14 (s, 3H), 0.91 (s, 3H).

Synthetic Example 12.16 Synthesis of4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzoicacid (Compound Ia-64) and4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzoicacid (Compound Ia-65)

Following the procedure as described in Synthetic Example 12 and makingnon-critical variations using 4-hydrazineylbenzoic acid hydrochloride toreplace phenyl hydrazine, the title compounds,4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzoicacid (Compound Ia-64) and4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzoicacid (Compound Ia-65), were obtained after purification by preparativeHPLC (Method 3a).

Compound Ia-64: LCMS: (Method 1d) MS m/z: 464 (M+1), t_(R): 1.65 min,Purity: 94.1% (UV).

HPLC: (Method 2b) t_(R): 6.41 min, Purity: 93.5% (UV).

¹H-NMR (400 MHz, CD₃OD): δ8.10 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz,2H), 7.51 (s, 1H), 4.70 (s, 2H), 3.91 (d, J=8.8 Hz, 1H), 3.54 (dd,J=2.0, 14.2 Hz, 1H), 3.44 (t, J=9.6 Hz, 1H), 3.39-3.20 (m, 1H),3.21-3.14 (m, 2H), 2.80-2.71 (m, 2H), 2.64-2.55 (m, 1H), 2.47 (d, J=16.0Hz, 1H), 2.41-2.32 (m, 1H), 2.22-2.01 (m, 2H), 1.99-1.85 (m, 2H),1.75-1.59 (m, 2H), 1.53-1.41 (m, 1H), 1.39-1.25 (m, 2H), 1.13 (s, 3H),0.87 (s, 3H).

Compound Ia-65: LCMS: (Method 1d) MS m/z: 464 (M+1), t_(R): 1.58 min,Purity: 97.3.91% (UV).

HPLC: (Method 2b) t_(R): 6.49 m %, Purity: 98.4% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 8.04 (d, J=8.4 Hz, 2H), 7.94 (s, 11H), 7.66(d, J=8.4 Hz, 2H), 4.70 (s, 2H), 3.96 (d, J=10.0 Hz, 11H), 3.47 (q,J=14.0 Hz, 2H), 3.32-3.19 (m, 3H), 2.78 (d, J=16.0 Hz, 11H), 2.65-2.50(m, 2H), 2.38-2.33 (in, 11H), 2.22-2.20 (in, 1H), 2.14-1.99 (m, 2H),1.95-1.85 (m, 2H), 1.80-1.65 (m, 2H), 1.58-1.25 (m, 3H), 1.11 (s, 3H),0.91 (s, 3H).

Synthetic Example 13 Synthesis of((5aS,6R,7S,9aS)-7-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridin-6-yl)methanol(Compound Ia-43) and((5R,6S)-5-((5aS,6R,7S,9aS)-6-(aminomethyl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridin-7-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-44)

Synthetic Example 13 Continued

A. Compound 84 (as prepared in U.S. Pat. No. 9,765,085) was converted to(2S,4aR,4bS,6aS,9aS,9bR,9cR,12aR,12bS)-2-((tert-butyldiphenysilyl)oxy)-4a,6a,11,11-tetramethylhexadecahydro-7H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7-oneoxime (Compound 85) through oxime formation.

B. Compound 85 was deprotected under acidic conditions to form(3S,5S,6R,7R,8R,9S,10R,13S,14S)-3-((tert-butydiphenylsilyl)oxy)-6,7-dihydroxy-10,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-oneoxime (Compound 86).

C.(3S,5S,6R,7R,8R,9S,10R,13S,14)-3-((ter-butydiphenylsilyl)oxy)-17-(hydroxyimino)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-6,7-diyldiacetate (Compound 87) was prepared by acetylating the diol, Compound86.

D. Compound 87 was converted to(3S,5S,6R,7R,8R,9S,10R,13S,14S)-17-acetamido-3-((tert-butyldiphenylsilyl)oxy)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-6,7-diyldiacetate (Compound 88) using acetic anhydride under basic conditions.

E. Compound 88 was treated with POCl₃ which cyclized to form achloropyridine, while the TBDPS alcohol protecting group wassimultaneously removed to form(1R,2R,2aS,4S,6aR,6bS,8aS,13aS,13bR)-10-chloro-4-hydroxy-6a,8a-dimethyl-2,2a,3,4,5,6,6a,6b,7,8,8a,13,13a,13b-tetradecahydro-1H-naphtho[2′,1′:4,5]indeno[1,2-b]pyridine-1,2-diyldiacetate (Compound 89).

F. Compound 89 was oxidized to form the ketone,(1R,2R,2aS,6aR,6bS,8aS,13aS,13bR)-10-chloro-6a,8a-dimethyl-4-oxo-2,2a,3,4,5,6,6a,6b,7,8,8a,13,13a,13b-tetradecahydro-1H-naphtho[2′,1′:4,5]indeno[1,2-b]pyridine-1,2-diyldiacetate (Compound 90).

G. Compound 90 underwent a Knoevenagel condensation to form(1R,2R,2aS,6aR,6bS,8aS,13aS,13bR)-10-chloro-1,2-dihydroxy-5-(hydroxymethylene)-6a,8a-dimethyl-1,2,2a,3,5,6,6a,6b,7,8,8a,13,13a,13b-tetradecahydro-4H-naphtho[2′,1′:4,5]indeno[1,2-b]pyridin-4-oneCompound 91.

H.(5aS,5bR,6R,7R,7aS,12aR,12bS,14aS)-2-chloro-12a,14a-dimethyl-5,5a,5b,6,7,7a,8,9,12,12a,12b,13,14,14a-tetradecahydropyrido[2″,3″:3′,4′]cydopenta[1′,2′:5,6]naphtho[1,2-f]indazole-6,7-diol(Compound 92) was obtained from the treatment of Compound 91 withhydrazine.

LCMS: (Method 1e) MS m/z: 414.2 (M+1), t_(R): 2.682 min, Purity: 76.30%(UV).

¹H-NMR (400 MHz, DMSO-dB): δ 12.20 (broad s, 1H), 7.66 (d, J=7.8 Hz,1H), 7.19 (d, J=7.8 Hz, 2H), 4.68 (d, J=3.8 Hz, 1H), 4.60 (d, J=4.4 Hz,1H), 3.40 (m, 1H), 3.17-2.92 (m, 4H), 2.08-2.01 (m, 3H), 1.92-1.59 (m,3H), 1.40-1.35 (m, 2H), 1.10-0.87 (m, 5H), 0.61-0.57 (m, 1H), 0.39 (s,3H).

I.(5aS,5bR,6R,7R,7aS,12aR,12bS,14aS)-12a,14a-dimethyl-5,5a,5b,6,7,7a,8,9,12,12a,12b,13,14,14a-tetradecahydropyrdo[2″,3″:3′,4′]cyclopenta[1′,2′:5,6]naphtho[1,2-f]indazole-6,7-diol(Compound 93) was obtained from the reduction of Compound 92.

LCMS: (Method 1e) MS m/z: 380.2 (M+1), t_(R): 2.140 min, Purity: 97.24%(UV).

HPLC: (Method 2e) t_(R): 4.135 min, Purity: 99.95% (UV).

¹H-NMR (400 MHz, MeOH-d4): δ 8.29 (d, J=5.2 Hz, 1H), 7.65 (d, J=7.2 Hz,1H), 7.28 (s, 1H), 7.16-7.19 (m, 1H), 3.47 (d, J=16.8 Hz, 1H), 3.23-3.35(m, 3H), 3.11 (dd, J=5.2, 16.4 Hz, 1H), 2.60-2.66 (m, 2H), 2.13-2.28 (m,3H), 1.74 (d, J=12.0 Hz, 1H), 1.75-1.59 (m, 2H), 1.11-1.20 (m, 5H), 0.82(q, J=13.2 Hz, 1H), 0.52 (s, 3H).

J. Compound 93 was opened using periodate to generate(5aS,6R,7S,9aS)-7-((5R,6S)-6-formyl-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridine-8-carbaldehyde(Compound 94).

K. Title compound((5aS,6R,7S,9aS)-7-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridin-6-yl)methanol(Compound Ia-43) was obtained from the sodium borohydride reduction ofCompound 94.

LCMS: (Method 1d) MS m/z: 382.2 (M+1), t_(R): 0.327 min, Purity: 99.43%(ELSD).

L. Title compound((5R,6S)-5-((5aS,6R,7S,9aS)-6-(aminomethyl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridin-7-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-44) was obtained from the conversion of Compound Ia-43, asper the scheme above.

LCMS: (Method 1h) MS m/z: 381.3 (M+1), t_(R): 1.673 min, Purity: 97.537%(UV).

Synthetic Example 14 Synthesis of(4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone(Compound Ia-45) and(4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone(Compound Ia-46)

A.(1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexylacetate (Compound 95, as prepared in U.S. Pat. No. 7,601,874) wasconverted to the mesylate(1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((1S,3aS,4S,5S,7aR)-1,7a-dimethyl-4-(((methylsulfonyl)oxy)methyl)octahydro-1H-inden-5-yl)-4-methylcyclohexylacetate (Compound 96) using mesyl chloride in pyridine.

B. Compound 96 was converted to the azide(1S,3S,4R)-4-((1S,3aS,4S,5S,7aR)-4-(azidomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcydohexylacetate (Compound 97) using sodium azide in DMF.

C. Compound 97 was deprotected under mild basic conditions to obtain(1S,3S,4R)-4-((1S,3aS,4S,5S,7aR)-4-(azidomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexan-1-ol(Compound 98).

D. Compound 98 was oxidized to the ketone(3S,4R)-4-((1S,3aS,4S,5S,7aR)-4-(azidomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexan-1-one(Compound 99) using TPAP and NMO.

E. Compound 99 underwent a Knoevenagel condensation with sodiummethoxide and ethyl formate to obtain(4R,5S)-4-((1S,3aS,4S,5S,7aR)-4-(azidomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(hydroxymethylene)-4-methylcyclohexan-1-one(Compound 100).

F. Compound 100 was reacted with (4-hydrazineylphenyl)(phenyl)methanoneto generate(4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(azidomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone(Compound 101a) and(4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(azidomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone(Compound 101b) as a mixture.

G. Title compound(4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone(Compound Ia-45) and title compound(4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone(Compound Ia-46) were obtained as pure compounds by deprotection andreduction of the mixture of Compounds 101a and 101b.

Compound Ia-45: LCMS: (Method 1c) MS m/z: 526.3 (M+1), t_(R): 2.704 min,Purity: 91.11% (UV).

Compound Ia-46: LCMS: (Method 1c) MS m/z: 526.3 (M+1), t_(R): 2.773 min,Purity: 92.41% (UV).

Synthetic Example 14.1 Synthesis of((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-47) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-48)

Following the procedure as described in Synthetic Example 14 and makingnon-critical variations using 4-fluorophenylhydrazine to replace(3-hydrazineylphenyl)(phenyl)methanone in the conversion of Compound 100to the mixture of Compounds 101a and 101b, the title compounds((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-47) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-48) were obtained.

Compound Ia-47: LCMS: (Method 1c) MS m/z: 440.2 (M+1), t_(R): 2.494 min,Purity: 97.38% (UV).

Synthetic Example 14.2 Synthesis of((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-49) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-50)

Following the procedure as described in Synthetic Example 14 and makingnon-critical variations using 4-methoxyphenylhydrazine to replace(3-hydrazineylphenyl)(phenyl)methanone in the conversion of Compound 100to the mixture of Compounds 101a and 101b, the title compounds((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-49) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-50) were obtained.

Compound Ia-49: LCMS: (Method 1c) MS m/z: 452.2 (M+1), t_(R): 2.428 min,Purity: 95.12% (UV).

Synthetic Example 14.3 Synthesis of((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-51) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-52)

Following the procedure as described in Synthetic Example 14 and makingnon-critical variations using 4-methoxybenzylhydrazine to replace(3-hydrazineylphenyl)(phenyl)methanone in the conversion of Compound 100to the mixture of Compounds 101a and 101b, the title compounds((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-51) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-52) were obtained.

Compound Ia-52: LCMS: (Method 1c) MS m/z: 466.3 (M+1), t_(R): 2.381 min,Purity: 99.94% (UV).

Synthetic Example 15 Synthesis of((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-54),((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-55) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanolhydrochloride (Compound Ia-55-HCl)

A. Using General Procedure S with2,2,2-trifluoro-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)acetamide(Compound 102 as prepared in U.S. Pat. No. 10,100,056, 20.0 g, 47.9mmol), Pd/C (5-10%, 2.0 g (w/w)), and EtOAc:MeOH (1:9, 200 mL) gave2,2,2-trifluoro-N-(((1S,3aS,4S,5S,7aR)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)acetamide(Compound 103, 17.4 g, 87%) as an off white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 0-5%MeOH/DCM).

LCMS: (Method 1d) MS m/z: 418 (M−1), t_(R): 2.24 min, Purity: 99.4%(UV).

B. Using General Procedure B with2,2,2-trifluoro-N-(((1S,3aS,4S,5S,7aR)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)acetamide(Compound 103, 17.4 g, 41.5 mmol), imidazole (4.20 g, 62.3 mmol), TBSCl(7.47 g, 49.8 mmol) and DMF (170 mL) gaveN-(((1S,3aS,4S,5S,7aR)-5-((1R,2S,4S)-2-(((tert-butydimethylsilyl)oxy)methyl)-4-hydroxy-1-methylcyclohexyl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide(Compound 104, 9.50 g, 43%) as a white solid after purification bycolumn chromatography on silica gel (230-400 mesh, 20-30% pet.ether/EtOAc).

LCMS: (Method 1d) MS m/z: 520 (M+1), t_(R): 3.86 min, Purity: 99.6%(ELSD).

C. Using General Procedure L withN-(((1S,3aS,4S,5S,7aR)-5-((1R,2S,4S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy-1-methylcyclohexyl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide(Compound 104, 9.50 g, 17.8 mmol), NMO (4.80 g, 35.6 mmol), 4 Åmolecular sieves (9.00 g), TPAP (1.20 g, 3.5 mmol) and DCM (100 mL) gaveN-(((1S,3aS,4S,5S,7aR)-5-((1R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-4-oxocyclohexyl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide(Compound 105, 8.00 g, 82%) as an off white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 10-15% pet.ether/EtOAc).

LCMS: (Method 1c) MS m/z: 514 (M+1), t_(R): 3.29 min, Purity: 97.5%(UV).

D. Following the General Procedure N withN-(((1S,3aS,4S,5S,7aR)-5-((1R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-4-oxocyclohexyl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide(Compound 105, 8.00 g, 15.1 mmol), NaH (60%, 2.90 g, 60.2 mmol), ethylformate (7.3 mL, 90.4 mmol) and THF (80 mL) gaveN-(((1S,3aS,4S,5S,7aR)-5-((1R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(hydroxymethylene)-1-methyl-4-oxocyclohexyl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trfluoroacetamide(Compound 106, 7.00 g, 83%) as a white solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 5-10% pet.ether/EtOAc).

LCMS: (Method 1c) MS m/z: 560 (M+1), t_(R): 3.38 min, Purity: 84.3%(UV).

E. Following the General Procedure O withN-(((1S,3aS,4S,5S,7aR)-5-((1R,2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(hydroxymethylene)-1-methyl-4-oxocyclohexyl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide(Compound 106, 4.00 g, 7.15 mmol) in EtOH (40 mL), TEA (2.00 mL, 14.3mmol) and (4-(4-fluorophenoxy)phenyl)hydrazine hydrochloride (asprepared in U.S. Pat. No. 6,919,363 or 7,078,426, 1.80 g, 7.15 mmol)gave bothN-(((1S,3aS,4S,5S,7aR)-5-((5R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide(Compound 107a) andN-(((1S,3aS,4S,5S,7aR)-5-((5R,6S)-6-(((tert-butydimethylsilyl)oxy)methyl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide(Compound 107b, 3.00 g, 56%) as a brown solid after purification bycolumn chromatography (230-400 mesh silica gel, eluted with 20-30% petether/EtOAc).

LCMS: (Method 1c) MS m/z: 742 (M+1), t_(R): 2.90 min, Purity: 78.4%(UV).

F. Following the General Procedure P with bothN-(((1S,3aS,4S,5S,7aR)-5-((5R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide(Compound 107a) andN-(((1S,3aS,4S,5S,7aR)-5-((5R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide(Compound 107b, 3.00 g, 4.04 mmol), TBAF (1 M in THF, 8.0 mL, 8.0 mmol)and THF (30 mL), gave both2,2,2-trifluoro-N-(((1S,3aS,4S,5S,7aR)-5-((5R,6S)-1-(4-(4-fluorophenoxy)phenyl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)acetamideand2,2,2-trifluoro-N-(((1S,3aS,4S,5S,7aR)-5-((5R,6S)-2-(4-(4-fluorophenoxy)phenyl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)acetamide,1.50 g, 59%) as off white solids after purification by columnchromatography (230-400 mesh silica gel, eluted with 30-50% petether/EtOAc).

LCMS: (Method 1c) MS m/z: 628 (M+1), t_(R): 3.53 min, Purity: 99.9%.

G. Following the General Procedure K with both2,2,2-trifluoro-N-(((1S,3aS,4S,5S,7aR)-5-((5R,6S)-1-(4-(4-fluorophenoxy)phenyl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-4-yl)methyl)acetamideand,2,2-trifluoro-N-(((1S,3aS,4S,5S,7aR)-5-((5R,6S)-2-(4-(4-fluorophenoxy)phenyl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-2H-inden-4-yl)methyl)acetamide(from F above, 1.50 g, 2.39 mmol), K₂CO₃ (0.65 g, 4.78 mmol) and MeOH(15 mL), gave both((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-55, 0.8 g, 63%) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-54) as an off white solid after purification by columnchromatography (230-400 mesh silica gel, eluted with 0-5% MeOH/DCM).

Compound Ia-55: LCMS: (Method 11) MS m/z: 532 (M+1), t_(R): 2.75 min,Purity: 98.3% (UV).

HPLC: (Method 2a) t_(R): 4.66 min, Purity: 98.1% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 7.51-7.44 (m, 3H), 7.16-7.06 (m, 6H), 3.93(dd, J=2.4, 10.8 Hz, 1H), 3.38 (t, J=10.0 Hz, 1H), 3.17 (d, J=14.0 Hz,1H), 3.08 (dd, J=5.6, 17.2 Hz, 1H), 2.78-2.58 (m, 3H), 2.41 (d, J=16.0Hz, 1H), 2.15-2.07 (m, 1H), 1.86-1.62 (m, 6H), 1.51-1.44 (m, 3H),1.29-1.24 (m, 2H), 1.11 (s, 3H), 1.02-0.98 (m, 1H), 0.88-0.86 (m, 3H),0.65 (s, 3H).

H. Following the General Procedure T with((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-55, 0.100 g, 0.188 mmol), HCl in diethyl ether (2M, 0.5 mL)and MeOH (1 mL), gave the desired((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanolhydrochloride (Compound Ia-55-HCl, 0.030 mg, 28%) as an off white solidafter drying.

LCMS: (Method 1c) MS m/z: 532 (M+1), t_(R): 2.15 min, Purity: 99.4%(UV).

HPLC: (Method 2a) t_(R) ^(: 4.70) min, Purity: 96.1% (UV).

¹H-NMR (400 MHz, DMSO-d6): δ 7.81 (s, 3H), 7.59 (d, J=8.8 Hz, 2H), 7.44(s, 1H), 7.27 (t, J=8.7 Hz, 2H), 7.17-7.10 (m, 4H), 3.75-3.69 (m, 1H),3.46-3.30 (m, 1H), 3.21 (t, J=9.9 Hz, 1H), 3.01-2.82 (m, 2H), 2.68-2.33(m, 2H), 2.40-2.30 (m, 1H), 1.91-1.63 (m, 7H), 1.41-1.39 (m, 2H),1.27-1.18 (m, 4H), 1.02 (s, 3H), 0.94-0.87 (m, 1H), 0.82 (d, J=6.4 Hz3H), 0.57 (s, 3H).

Synthetic Example 15.1 Synthesis of((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-2-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-56) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-2-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-57)

Following the procedure as described in Synthetic Example 15 and makingnon-critical variations using 2-(4-hydrazineylphenoxy)pyridinehydrochloride (as prepared in PCT Published Patent Application No. WO2009/117421) in place of (4-(4-fluorophenoxy)phenyl)hydrazinehydrochloride in Step E, the title compounds((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-2-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-56) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-57) were obtained.

Compound Ia-57: LCMS: (Method 1c) MS m/z: 515 (M+1), t_(R): 1.80 min,Purity: 98.1% (UV).

HPLC: (Method 2a) t_(R): 3.90 min, Purity: 93.7% (UV).

¹H-NMR (400 MHz, CD₃OD): δ 8.14 (d, J=3.6 Hz, 1H), 7.87-7.28 (m, 1H),7.57-7.55 (m, 2H), 7.46 (s, 1H), 7.25-7.22 (m, 2H), 7.14 (t, J=6.0 Hz,1H), 7.01 (d, J=8.4 Hz, 1H), 3.92 (d, J=10.0 Hz, 1H), 3.39 (t, J=10.0Hz, 1H), 3.29-3.09 (m, 1H), 2.93-2.89 (m, 1H), 2.74-2.62 (m, 2H), 2.43(d, J=16.0 Hz, 1H), 2.11 (s, 1H), 1.88-1.71 (m, 4H), 1.66-1.48 (m, 3H),1.39-1.27 (m, 4H), 1.10-1.03 (m, 4H), 0.89-0.86 (m, 4H), 0.66 (s, 3H).

Synthetic Example 15.2 Synthesis of((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-58), and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-59)

Following the procedure as described in Synthetic Example 15 and makingnon-critical variations using 4-(4-hydrazineylphenoxy)pyridinehydrochloride (as prepared in U.S. Published Patent Application No.2009/0253688) in place of (4-(4-fluorophenoxy)phenyl)hydrazinehydrochloride in Step E, the title compounds((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-58), and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-59) were obtained.

Compound Ia-58: LCMS: (Method 1c) MS m/z: 515 (M+1), t_(R): 1.59 min,Purity: 98.2% (UV).

HPLC: (Method 2a) t_(R): 3.17 min, Purity: 98.2% (UV).

¹H-NMR (400 MHz, DMSO-d6): δ 8.50 (d, J=6.0 Hz, 2H), 7.71 (d, J=8.8 Hz,2H), 7.48 (s, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.00 (d, J=6.0 Hz, 2H), 4.53(s, 1H), 3.74 (d, J=9.9 Hz, 1H), 3.21-3.09 (m, 4H), 2.76-2.60 (m, 4H),2.34-2.29 (m, 1H), 2.05-1.99 (m, 1H), 1.77-1.61 (m, 6H), 1.41-1.36 (m,3H), 1.24-1.13 (m, 2H), 1.04 (s, 3H), 1.01-0.87 (m, 1H), 0.87 (d, J=5.6Hz, 3H), 0.57 (s, 3H).

Compound Ia-59: LCMS: (Method 1c) MS m/z: 515 (M+1), t_(R): 1.58 min,Purity: 98.5% (UV).

HPLC: (Method 2a) t_(R): 3.15 min, Purity: 97.5% (UV).

¹H-NMR (400 MHz, DMSO-d6): δ 8.48 (dd, J=1.4, 4.8 Hz, 2H), 8.15 (s, 1H),7.85 (d, J=8.9 Hz, 2H), 7.28 (d, J=8.9 Hz, 2H), 6.95 (dd, J=1.4, 4.8 Hz,2H), 4.52 (s, 1H), 3.76 (d, J=9.7 Hz, 1H), 3.24-3.11 (m, 3H), 3.10-3.06(m, 1H), 2.83-2.80 (m, 1H), 2.68-2.56 (m, 2H), 2.38-2.34 (m, 1H),2.09-1.97 (m, 1H), 1.78-1.63 (m, 6H), 1.49-1.13 (m, 6H), 1.00 (s, 3H),0.94-0.90 (m, 1H), 0.83 (d, J=6.6 Hz, 3H), 0.58 (s, 3H).

Synthetic Example 15.3 Synthesis of((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-60), and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-61)

Following a portion of the procedure as described in Synthetic Example15 and making non-critical variations 5-(4-hydrazineylphenoxy)pyrimidinehydrochloride (prepared from known methods as in U.S. Published PatentApplication No. 2009/0253688 or PCT Published Patent Application No. WO2009/117421) in place of hydrazine hydrate in Step E, the respectivetitle compounds,((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol(Compound Ia-60) and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol(Compound Ia-61), were obtained.

Compound Ia-60: LCMS: (Method 1c) MS m/z: 516 (M+1), t_(R): 1.78 min,Purity: 99.2% (UV).

HPLC: (Method 2a) t_(R): 3.67 min, Purity: 95.1% (UV)

¹H-NMR (400 MHz, DMSO-d): δ 9.04 (s, 1H), 8.71 (s, 2H), 7.66 (d, J=8.8Hz, 2H), 7.46 (s, 1H), 7.30 (d, J=8.8 Hz, 2H), 4.50 (s, 1H), 3.73 (d,J=9.2 Hz, 1H), 3.22-3.17 (m, 1H), 3.09-3.06 (m, 2H), 2.69-2.59 (m, 4H),2.33-2.26 (m, 1H), 2.05-1.91 (m, 1H), 1.77-1.51 (m, 7H), 1.42-1.39 (m,3H), 1.19-1.15 (m, 2H), 1.04 (s, 3H), 0.92-0.86 (m, 1H), 0.82 (d, J=6.8Hz, 3H), 0.56 (s, 3H).

Compound Ia-61: LCMS: (Method 1c) MS m/z: 516 (M+1), t_(R): 1.84 min,Purity: 99.8% (UV).

HPLC: (Method 2a) t_(R): 3.74 min, Purity: 92.6% (UV).

¹H-NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.65 (s, 2H), 8.13 (s, 1H),7.81 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 4.52 (s, 1H), 3.77-3.75(m, 1H), 3.24-3.17 (m, 2H), 3.10-3.04 (m, 1H), 2.83-2.80 (m, 1H),2.68-2.60 (m, 2H), 2.51-2.33 (m, 2H), 2.11-2.03 (m, 1H), 1.78-1.63 (m,6H), 1.49-1.17 (m, 6H), 1.00 (s, 3H), 0.98-0.84 (m, 1H), 0.83 (d, J=6.5Hz, 3H), 0.57 (s, 3H).

Biological Example 1

Rat Dorsal Root Ganglion Excitability Response of RepresentativeCompounds Dorsal root ganglions (DRGs) were dissected from adult rats.The tissue was processed, and cells were seeded into cell culture plates(48 center wells of one quadrant in 384-well plates) and cultured for 2days prior to Electrical field stimulation (EFS). To visualize theneuronal excitability response, intracellular Ca⁺² transients weremonitored using the Ca⁺² indicator, Ca5. Ca5 was added to the cultures 1h prior to EFS. Representative compounds of the invention (i.e., testcompounds) and reference compound, tetracaine, were added inconcentration-response format encompassing six concentrations, performedin duplicate. The highest concentration tested was typically 30 μM with1 in 3 dilutions generating the subsequent concentrations.

Effects on DRG excitability by the test compounds and standard wereevaluated using four EFS protocols as disclosed in Table 2.

TABLE 2 EPS PROTOCOL PARAMETERS Protocol Voltage Frequency Pulseduration # # (V) (Hz) (ms) of pulses 1 20 5 0.3 25 2 20 30 0.3 150 3 305 0.3 25 4 30 30 0.3 150

Experimental results were performed using two seperate sets of platesusing separate test compound and standard dilutions, to provide n=2. Inthe first set of experiments, compounds were added 24 h prior to EFS toincrease the possibility to also detect more long-term compound effects.In the second set of experiments the compounds were added directly priorto EFS. Excitability response to EFS was analyzed as the averagefluorescence ratio (peak/baseline) change per well. All plates wereevaluated using high content imaging equipment post-EFS, imaging the Ca5background staining to detect any possibile compound-related toxiceffects.

According to the above assay, the representative compounds listed inTable 3 below were found to modulate rat DRG excitability at theconcentrations indicated. Average response by the reference compound,tetracaine, was 4.05 μM. Scoring for the representative compounds was asfollows: “A” represents an EC₅₀ below 2 μM, “B” represents an EC₅₀between 2 and 6 NM, “C” represents an EC₅₀ between 6 and 15 μM and “D”represents an EC₅₀ above 15 μM.

TABLE 3 Cpd. No. Scoring Ia-24 A Ia-22 A Ia-12 A Ia-20 A Ia-40 B Ia-34 BIa-23 B Ia-30 B Ia-32 B Ia-25 B Ia-13 B Ia-38 B Ia-14 B Ia-6  B Ia-26 CIa-15 C Ia-27 C Ia-2  C Ia-17 B Ia-18 A Ia-52 A Ia-28 A Ia-29 A Ia-49 BIa-36 D Ia-47 A

Biological Example 2 T Cell Proliferation and Cytokine Release Activityof Representative Compounds Spleens were Obtained from Six Male, CD-1Outbred Mice, Approximately 8

weeks old. Cells were harvested under sterile conditions by forcing eachspleen though a cell filter (pore size 100 μm diameter). A homogenouscell suspension was obtained by washing the cells in fresh medium andpassing cells through a smaller cell filter (pore size 70 μm).

Untouched T cells were isolated using the Pan T cell isolation kit(Miltenyi Biotech). Briefly, cells were counted and incubated with therequired volume of antibody cocktail for 5 minutes at 4° C. beforeaddition of microbeads and incubation for 10 minutes at 4° C. Labeledcells were retained in a magnetic column while unlabeled cells (T cells)passed through the column and were retained for use in the assay.

Cell viability was assessed by Trypan Blue exclusion and found tobe >99% prior to transfer to plates. Isolated T cells were seeded out in96 well plates at a density of 50,000 cells per well and allowed toincubate for 60 minutes in a humidified cell culture (37° C., 5% CO₂)incubator prior to compound treatment. The media used for this assay(TexMACS, Miltenyi Biotech) was previously optimized for proliferationof T cells in serum free conditions.

Representative compounds of the invention (i.e., test compounds) wereprepared as 30 mM stocks in 100% DMSO. Test compounds were initiallydiluted in media to yield 3 mM stocks before an additional 1:10 dilutionin media was performed to yield working stocks of 300 μM (1% DMSO).Subsequent dilutions were performed in media (supplemented with 1%DMSO). When added to the assay plates (1:10 dilution), these yieldedfinal concentrations in the assay plates of in 0.1% DMSO. The referencecompound, Cyclosporin A, was prepared in an identical manner as above.

Unstimulated and Stimulated Control wells received an identical volumeof TexMACS media/1% DMSO at this time, resulting in a finalconcentration of 0.1% DMSO across the plate. Mouse anti-CD3/anti-CD28dynabeads were prepared (following the manufacturers' instructions) inTexMACS media and added to appropriate wells to achieve a finalconcentration of 1 bead per cell. Unstimulated Control wells thenreceived an identical volume of TexMACS. Plates were centrifuged 72hours after addition of dynabeads, (300×g for 3 minutes) to pellet thecells and 60% of the supernatant was removed to a fresh plate foranalysis by ELISA. After removal of 60% of the supernatant forsubsequent ELISA, cell proliferation was assessed using the CCK-8 assay.

According to the above assay, the representative compounds of theinvention listed in Table 4 below were found to modulate cellproliferation at the concentrations indicated. Average response by thestandard compound, cyclosporin A, was 1 μM. Scoring for therepresentative compounds was as follows: “A” represents an IC₅₀ below0.5 μM, “B” represents an IC₅₀ between 0.5 and 1.5 μM, “C” represents anIC₅₀ between 1.5 and 15 μM and “D” represents an IC₅₀ above 15 μM.

TABLE 4 Cpd. No. Scoring Ia-1 C Ia-2 C Ia-9 C

Biological Example 3 Human Dorsal Root Ganglion (DRG) ExcitabilityResponse of Representative Compounds

Human DRGs are transferred into a dissection vessel containing a cold(4° C.), fresh proprietary dissection solution. DRGs are maintainedcompletely submerged in dissection solution followed by dissection by anappropriate method.

Cells are plated into a 96 well plate. Calcium dye (Fluo 8-AM) is loadedin each well for a period of 20 to 25 min, maintaining temperature atambient. The baseline excitability profile (ability of firing actionpotentials) of the cells is assessed at both low and high thresholdstimulations using optical EFS. Following baseline profiling, cells aresubjected to test compounds.

Representative compounds of the invention (i.e., test compounds) areadded to cells and the cells are stimulated (using EFS) to induce actionpotentials at regular intervals, according to the parameters outlined inTABLE 5. Four concentrations of each compound are utilized and directlyinjected into separate wells to allow for determination of a doseresponse (IC₅₀). At the end of the protocol, the nociceptor positivecontrol compound (capsaicin) is perfused into the cells at 200 nM andsignal recorded. TTX (300 nM) is also examined using this protocol in aseparate well.

TABLE 5 EPS PROTOCOL AND RECORDING SEQUENCE Action Parameter/DetailBaseline Low Voltage 2 s recording with stimulation (5 Hz) Rest 3 minBaseline High Voltage 2 s recording with stimulation (5 Hz)Preincubation of 5 min Test compounds Test Compound Low 2 s recordingwith stimulation (5 Hz) Votage Signal Rest 3 min Test Compound High 2 srecording with stimulation (5 Hz) Votage Signal Washout 5 min Capsaicin20 s (recording 3 min)

Recordings are performed in stream mode at 100 Hz for the EFS portion ofthe above protocol and in time lapse model at 0.2 Hz for the final steputilizing capsaicin. For each concentration tested, the number of cellsblocked vs baseline will be counted at different thresholds.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate human DRG excitability.

Biological Example 4 Pulmonary LPS Challenge Assay of RepresentativeCompounds in Mice

Mice (male, C57B116) are acclimatized for a period of about 7 daysbefore initiation of the experiment and are randomized on the day priorto treatment. Mice receive vehicle or a representative compound of theinvention (i.e., test compound) once daily for three days by oral gavageon Day −2, Day −1 and on Day 0 (the last dose being 1 h prior to LPSadministration). One group of mice receive the reference standard,dexamethasone, once, IP on Day 0 at 1 h prior to LPS administration.Pulmonary inflammation is induced in all animals except the sham controlanimals by intratracheal instillation of 20 μg LPS per animal in 50 μlsaline. Sham control animals receive 50 μl saline alone.

Twenty-four hours post LPS administration, animals are euthanized andthe trachea is cannulated. Cold Hanks Balanced Salt Solution (SIGMA;Catalogue number: H1387), pH 7.2, is infused into the lungs andbronchoalveolar lavage fluid (BALF) is collected.

Total leukocyte counts are performed from the collected BALF using amini flow-cytometer and differential counts are performed in cytospinsmears stained with Leishman's staining manually. ELISA kits are usedfor quantification of cytokines in the BALF (TNFα, IL-10, IL-6 and KC).Reagents, samples and standards are prepared as per kit manual. Totalprotein analysis in BALF samples is performed using the Biorad proteinassay reagent.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate inflammatory markers in BALF, indicating theirefficacy against LPS-induced inflammation.

Biological Example 5 Formalin Pain Assay of Representative Compounds inMice

Mice (male, C57BL/6) were placed singly in a Perspex chamber forapproximately 30 min on three successive days to acclimate and therebyreduce stress-induced behaviors. On the fourth day, the experimentalanimals received a 25 μl injection of 2.5% formalin beneath the leftplantar skin using a 29-gauge syringe. Animals were administeredvehicle, reference standard Tramadol or a representative compound of theinvention (i.e., test compound) prior to formalin injection. The totaltime spent on flinches/licking/biting of the hind paw was recorded byvisual observation for every 5 min period/interval for total observationduration of 60 min in two phases, the early phase (0-5 min) and the latephase (15-40 min). Observers were blinded to the treatment groupallocation.

According to the above assay, the test compounds listed in Table 6 belowwere active in the formalin pain assay in mice at the concentrationsindicated. Average AUC % Inhibition by the standard compound, tramadolwas 59%. For test compounds, % protection from 0-60 min was used toassess activity. Scoring for the test compounds was as follows: “A”represents a % protection of 81 to 100%, “B” represents a % protectionof 61 to 80%, “C” represents a % protection of 31 to 60% and “D”represents a % protection of 0 to 30%.

TABLE 6 Cpd. No. Scoring Ia-10a and Ia-10b C Ia-2 D

Biological Example 6 TNBS Colitis Assay of Representative Compounds inRats

Rats (male, Sprague-Dawley) are anaesthetized and a solution of TNBS (48mg/kg) in ethanol, is instilled intra-rectally to induce colitis, 1 hafter oral dosing of representative compounds of the invention (i.e.,test compounds). Test compounds are dosed PO (by mouth, per os), QD(once of day, quaque die) for 7 days, using prednisolone as a referencestandard. Rats are observed for body weight loss and fecal output. OnDay 7, rats are euthanized and the colon are evaluated for length,weight, wall thickness, ulcer number and length and for the presence ofadhesions and strictures. A colonic score is calculated based on theseverity of the colonic parameters.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate colonic parameters, indicating their efficacyagainst colitis.

Biological Example 7 Cyclophosphamide-Induced Cystitis in Rats (VisceralPain)

Representative compounds of the invention (i.e., test compounds) areadministered to female Sprague-Dawley rats, for four days by oral gavagein 0.9% saline. Two hours after the fourth dose, the rats are challengedby intraperitoneal administration of cyclophosphamide (150 mg/kg).Referred mechanical sensitivity is measured four hours later by applyinga series of eight von Frey filaments to the lower abdomen, three timeseach for 1-2 seconds with a 5 second interval between applications.Responses are scored (zero-no response; one-response, two-response andchange of position, and three-response, change of position and lickingthe site or vocalization), totaled and the percent of maximal possiblenociceptive score calculated. Ibuprofen is used as a reference standard.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate nociceptive pain, indicating efficacy againstcystitis.

Biological Example 8 Rat Ketamine Cystitis (Visceral Pain)

Rats (female, Sprague-Dawley) receive daily intraperitoneal injectionsof saline (sham control) or ketamine (50 mg/kg) for 14 days.Representative compounds of the invention (i.e., test compounds) areadministered PO, QD starting on Day 0 at doses of 10, 3 or 1 mg/kg andTramadol is used as a reference control compound at 10 mg/kg.

Referred mechanical sensitivity is assessed on Day 7 and day 14 byapplication of a series of von Frey filaments to the lower abdomen andthe nociceptive threshold was scored.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate nociceptive pain and/or inflammation,indicating efficacy against cystitis.

Biological Example 9 Rat Chronic Prostatitis/Chronic Pelvic Pain (PelvicPain)

Representative compounds of the invention (i.e., test compounds) areadministered for 11 days by oral gavage in 0.9% saline (3, 10 or 30mg/kg QD; 5 mL/kg dose volume) to male Sprague-Dawley rats.Carrageenan-mediated chronic prostatitis/chronic pelvic pain (CP/CPPS)is established in rats (10 per group) by administration of anintraprostatic injection of carrageenan (˜12.5 μL/lobe of a 30 mg/mLsolution) into both ventral prostate lobes, on Day 0. Referredmechanical sensitivity is measured on Days 0, 1, 3 and 7, 2 hours aftertest compound or vehicle (saline) administration, by applying 6 von Freyfilaments with increasing forces of 0.16-2 g to the scrotal skin area, 3times each for 1-2 seconds, with a 5-second interval betweenapplications. Responses are scored (zero-no response; one-reaction ofthe animal, two-jump, and three-licking the site) and expressed as thenociceptive threshold for each day of assessment. Ibuprofen is used as areference standard.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate nociceptive pain, indicating efficacy againstchronic prostatitis/chronic pelvic pain.

Biological Example 10 Rat Monosodium Iodoacetate-Induced Osteoarthritis(Osteoarthritis/Inflammatory Pain)

Representative compounds of the invention (i.e., test compounds) areadministered to rats (male, Wistar) PO, QD, at 3 or 30 mg/kg, startingon Day 0 through to Day 21 of the study. Osteoarthritis is modeled byintra-articular injection of 3 mg of monosodium iodoacetate (MIA) in theright knee. Knee swelling, paw withdrawal threshold (mechanicalallodynia) and the difference in weight bearing are measured on Day 0(pre-induction) and on Days 3, 7, 14 and 21 post-MIA injection. Tramadolis used as a reference standard.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate knee swelling, paw withdrawal threshold anddifference in weight bearing, indicating efficacy againstosteoarthritis.

Biological Example 11 Complete Freund's Adjuvant (CFA) Model ofInflammatory Pain in Rats (Inflammatory Pain)

Representative compounds of the invention (i.e., test compounds) aretested in this model of inflammatory pain. The rats (male, Wistar) areacclimatized to the instruments (plantar test surface and dynamicplantar aesthesiometer) on two consecutive days prior to the initiationof the study. On Day 0, basal paw withdrawal latency and paw withdrawalthreshold are taken and animals are randomized to different groups.Complete Freund's Adjuvant (CFA) at 1 mg/mL (0.1 mL) was injected intothe plantar surface of right hind paw. Test compounds (3 or 30 mg/kg)are administered PO, twice (Day 0 and Day 1) or once, on Day 1 (24 hafter CFA). Thermal hyperalgesia and mechanical allodynia are assessedat 0 (baseline), 1, 3 and 6 h after administration of the test compoundon Day 1. Diclofenac is used as a reference compound, given once on Day1.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate inflammatory pain.

Biological Example 12 Rat Carrageenan-Induced Hyperalgesia and Paw Edema(Inflammatory Pain)

Representative compounds of the invention (i.e., test compounds) areadministered PO, QD, for 3 days prior to carrageenan injection, once at1 h prior to carrageen, or at 5 min or 1 h post-challenge to Rats (male,Sprague-Dawley). Rats receive either an intraplantar injection of saline(sham) or carrageen (0.1 mL of a 2% solution [w/v]) in the right hindpaw. Mechanical hyperalgesia (using an analgesymeter) and paw volume(using a digital plethysmometer) are measured at baseline (0 hr), 2, 4and 6 h post carrageenan injection for all the animals. Celecoxib, given1 h prior to carrageen challenge, is used as a reference standard.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate mechanical hyperalgesia and paw volume,indicating their efficacy against hyperalgesia.

Biological Example 13 Spinal Nerve Ligation (Neuropathic Pain)

Rats (male, Sprague-Dawley) are anaesthetized and placed in a proneposition and the left paraspinal muscles are separated from the spinousprocesses at the L6-S2 levels. The L6 transverse process is carefullyremoved to visually identify the L4-L6 spinal nerves. The left L5 spinalnerves are isolated and tightly ligated with 6-0 silk thread. The skinis sutured to close the open tissue and animals are allowed to recoverfor 1 week before pain assessment. Basal readings for mechanicalallodynia and thermal hyperalgesia are performed using a dynamic plantaraesthesiometer and plantar test surface, respectively, before surgery.On Day 7 following surgery, mechanical allodynia and thermalhyperalgesia are assessed and animals are randomized into treatmentgroups based on these baseline readings. From Day 7 to Day 14, the ratseither receive vehicle, tramadol (reference standard) or representativecompounds of the invention (i.e., test compounds). Thermal hyperalgesiaand mechanical allodynia are tested at 0, 60 and 120 minutes postadministration of compounds on Days 7 and 14.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate neuropathic pain.

Biological Example 14 Bleomycin Lung Fibrosis

Mice (male, C57BL/6) are randomized into treatment groups and fibrosisis induced by intratracheal administration of bleomycin. Treatment withrepresentative compounds of the invention (i.e., test compounds) orreference standard (pirfenidone) is initiated on Day −1 and administereddaily unto Day 7 or Day 21. For groups undergoing bronchoalveolar lavage(BAL), the trachea is cannulated and infused with ice cold Hank'sBalanced Salt Solution (HBSS, pH 7.2). The collected lavage fluid isanalyzed for cell numbers (total and differential counts) and levels ofsoluble TGFs and collagen. For other groups, the lungs are eithersnap-frozen or formalin-fixed for further analyses.

Compounds of the invention may be tested in this assay to determinetheir ability to modulate pulmonary inflammation and fibrosis.

Biological Example 15 Metabolism by Human Liver Microsomes

Representative compounds of the invention (i.e., test compounds) and thepositive control, 7-ethoxycoumarin, were prepared as stock solutions at10 mM in DMSO and eventually diluted to 10 μM in the test plate, with anappropriate amount of acetonitrile and tris HCl buffer. Final DMSO andacetonitrile concentrations were 0.01% and 0.5% respectively. NADPH wasprepared in tris HCl buffer to a stock of 10 mM. A frozen aliquot ofliver microsomes was retrieved from the freezer (−80° C.) and thawed byplacing the tube on wet ice. After thawing, the tubes were gently mixedand the required amount, transferred to tris HCl buffer. Test compoundsor positive control were pre-incubated, separately, for 10 minutes, withliver microsomes (1 mg/mL protein), at 37° C., in 100 mM Tris HCl at pH7.5. After preincubation the reaction was started by adding 1 mM NADPH(pre-equilibrated to 30° C.) and the reaction allowed to proceed for 60minutes. At 60 minutes, a 50 μL aliquot was removed and quenched with200 uL of acetonitrile containing a mixture of internal standards(Tolbutamide (500 ng/mL) and Telmistartan (500 ng/mL)) and vortexed thencentrifuged at 4000 rpm for 10 minutes (Eppendorf 5810R). Thesupernatant was transferred to a 96 well plate for LC-MS/MS analysis.

An LC-MS/MS method was devised for the test compounds and the control,using a AB Sciex API 4000 system coupled to a NEXAR™ UHPLC (Shimadzu)system. Analytes were separated on a Phenomenex Kinetex C18 column(50×2.1 mm, 5 μm) using a gradient that was appropriate for eachcompound, at a flow rate of 1 ml/minute, utilizing a mobile phase of0.1% formic acid in MILLI-Q™ water (A) and 0.1% formic acid inacetonitrile (B). The MS instrument was operated in positive mode(ESI+)/negative (ESI−). The multiple reaction monitoring (MRM)transition for test and control compounds was used for the LC-MS/MSanalysis. MRM transitions for control compound 7-ethoxycoumarinm wereQuadropole 1: 191.0, Quadropole 3:163.0, dwell time: 75 msec, usingcurtain gas settings of 5 V, ion-spray voltage of 5500 V, temperature of50° C. and gas settings for nebulizer and auxiliary set to 30 and 40psi, respectively. The interface heater was kept on. Entrance potentialand collision cell exit potential were varied to tune for a specificcompound.

Using a suitable LC-MS/MS method, the percentage of drug remaining at 60minutes (PCR60) was assessed by comparing the average analyte tointernal standard area ratio at 60 minutes to the average analyte tointernal standard area ratio at 0 time control, as a percentage, from a5 to 10 μL sample injection.

According to the above assay, the test compounds listed in Table 7 belowwere active in the Human liver microsome assay at 10 μM and the % ofdrug remaining after 60 minutes (PDR60), in the presence of NADPH, wasassessed by LC-MS/MS. Average PDR60 for the standard compound,7-ethoxycoumarin was <=65% in the presence of NADPH. Scoring for thetest compounds, in the presence of NADPH, was as follows: “A” representsa PDR60 of 81 to 100%, “B” represents a PDR60 of 61 to 80%, “C”represents a PDR60 of 31 to 60% and “D” represents a PDR60 of 0 to 30%.

TABLE 7 Cpd. No. Scoring Ia-2  A Ia-6  A Ia-7  B Ia-10a and Ia-10b CIa-12 D Ia-13 A Ia-14 D Ia-15 B Ia-17 C Ia-19 B Ia-20 B Ia-22 D Ia-23 CIa-24 B Ia-25 B Ia-26 D Ia-27 C Ia-28 B Ia-29 C Ia-30 D Ia-32 D Ia-34 DIa-36 A Ia-39 A Ia-40 D Ia-49 D Ia-52 A

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

1. A method of treating inflammation and/or pain inflammation and/orpain caused by colitis, cystitis, chronic prostatitis or chronic pelvicpain, osteoarthritis, inflammatory pain, hyperalgesia, neuropathic pain,and/or pulmonary inflammation or fibrosis, the method comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of formula (I), or a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt or solvate thereof, to a mammal in needthereof, wherein the mammal has inflammation and/or pain caused bycolitis, cystitis, chronic prostatitis or chronic pelvic pain,osteoarthritis, inflammatory pain, hyperalgesia, neuropathic pain,and/or pulmonary inflammation or fibrosis, wherein formula (I) is:

wherein:

is an optionally substituted fused 5- or 6-membered N-heteroaryl; R¹ ishydrogen; R² is —R⁶—OR⁷; R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂; R^(4a) is —R⁹—OR⁷and R^(4b) is hydrogen, alkyl or optionally substituted heteroaryl; orR^(4a) is an optionally substituted aryl and R^(b) is a bond to C16; orR^(4a) and R^(4b) together form alkylidene, provided that

is a fused 5- or 6-membered N-heteroaryl substituted by substitutedaryl, substituted aralkyl, substituted cycloalkyl or substitutedheteroaryl; or R^(4a) is alkyl and R^(4b) is hydrogen, provided that

is a fused 5- or 6-membered N-heteroaryl substituted by substitutedaryl, substituted aralkyl, substituted cycloalkyl or substitutedheteroaryl; or R⁴ and R¹ together form an optionally substitutedbicyclic heterocyclyl and R^(b) is hydrogen; or R^(4a), R^(4b) and R¹together form a fused optionally substituted heteroaryl; R⁵ is alkyl orR⁵ is a direct bond to the carbon at C14; each R⁶ is independentlyselected from a direct bond or a straight or branched alkylene chain;each R⁷ is independently selected from hydrogen or alkyl; each R⁸ isindependently selected from hydrogen or alkyl; and R⁹ is a direct bondor a straight or branched alkylene chain; or a stereoisomer, enantiomeror tautomer thereof or mixtures thereof, or a pharmaceuticallyacceptable salt or solvate thereof.
 2. The method of claim 1 wherein informula (I):

is an optionally substituted fused 5- or 6-membered N-heteroaryl; R¹ ishydrogen; R² is —R⁶—OR⁷; R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂; R⁴ is —R⁹—OR⁷ andR^(4b) is hydrogen, alkyl or optionally substituted heteroaryl; R⁵ isalkyl or R⁵ is a direct bond to the carbon at C14; each R⁶ isindependently selected from a direct bond or a straight or branchedalkylene chain; each R⁷ is independently selected from hydrogen oralkyl; each R⁸ is independently selected from hydrogen or alkyl; and R⁹is a direct bond or a straight or branched alkylene chain.
 3. The methodof claim 2 wherein the compound of formula (I) is selected from:(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol;(1R,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-ol;(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-1,7a-dimethyloctahydro-1H-inden-1-ol;(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol;(1S,3aS,4R,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol;(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol;and(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol.4. The method of claim 2 wherein the compound of formula (I) is:(2S,5R)-5-ethyl-2-((1R,3aS,4S,5S,7aS)-4-(hydroxymethyl)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyloctahydro-1H-inden-1-yl)-6-methylheptan-3-ol.5. The method of claim 1 wherein in formula (I):

is an optionally substituted fused 5- or 6-membered N-heteroaryl; R¹ ishydrogen; R² is —R⁶—OR⁷; R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂; R^(4a) and R¹together form an optionally substituted bicyclic heterocyclyl and R^(4b)is hydrogen; R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;each R⁶ is independently selected from a direct bond or a straight orbranched alkylene chain; each R⁷ is independently selected from hydrogenor alkyl; and each R⁸ is independently selected from hydrogen or alkyl.6. The method of claim 5 wherein the compound of formula (I) is selectedfrom:((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(hydroxymethyl)-3,3b,5′-trmethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;and((5R,6S)-5-((2R,3S,3aR,3bS,5′R,6S,7R,7aS,8aS)-7-(aminomethyl)-3,3b,5′-trmethyltetradecahydrospiro[indeno[2,1-b]furan-2,2′-pyran]-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.7. The method of claim 1 wherein in formula (I):

is an optionally substituted fused 5- or 6-membered N-heteroaryl; R¹ ishydrogen; R² is —R⁶—OR⁷; R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂; or R^(4a), R^(4b)and R¹ together form a fused optionally substituted heteroaryl; R⁵ isalkyl or R⁵ is a direct bond to the carbon at C14; each R⁶ isindependently selected from a direct bond or a straight or branchedalkylene chain; each R⁷ is independently selected from hydrogen oralkyl; and each R⁸ is independently selected from hydrogen or alkyl. 8.The method of claim 7 wherein the compound of formula (I) is selectedfrom:((4aS,5R,6S,8aS)-6-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-5-yl)methanol;((5R,6S)-5-((4aS,5R,6S,8aS)-5-(aminomethyl)-8a-methyl-1,4,4a,5,6,7,8,8a-octahydroindeno[1,2-c]pyrazol-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((5aS,6R,7S,9aS)-6-(aminomethyl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridin-7-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;and((5aS,6R,7S,9aS)-7-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-9a-methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridin-6-yl)methanol.9. The method of claim 1 wherein in formula (I):

is an optionally substituted fused 5- or 6-membered N-heteroaryl; R¹ ishydrogen; R² is —R⁶—OR⁷; R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂; R⁴ is anoptionally substituted aryl and R^(b) is a bond to C16. R⁵ is alkyl orR⁵ is a direct bond to the carbon at C14; each R⁶ is independentlyselected from a direct bond or a straight or branched alkylene chain;each R⁷ is independently selected from hydrogen or alkyl; and each R⁸ isindependently selected from hydrogen or alkyl.
 10. The method of claim 9wherein the compound of formula (I) is selected from:((5R,6S)-5-((3aS,6S,7R,7aS)-7-(aminomethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;and((5R,6S)-5-((3aS,6S,7R,7aS)-7-(hydroxymethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.11. The method of claim 1 wherein in formula (I):

is a fused 5- or 6-membered N-heteroaryl substituted by substitutedaryl, substituted aralkyl, substituted cycloalkyl or substitutedheteroaryl; R¹ is hydrogen; R² is —R⁶—OR⁷; R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;R^(4a) and R^(4b) together form alkylidene; R⁵ is alkyl or R⁵ is adirect bond to the carbon at C14; each R⁶ is independently selected froma direct bond or a straight or branched alkylene chain; each R⁷ isindependently selected from hydrogen or alkyl; and each R⁸ isindependently selected from hydrogen or alkyl.
 12. The method of claim11 wherein the compound of formula (I) is selected from:((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenoxy)benzoicacid;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-1-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-5-methyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(2,4-difluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;4-(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenoxy)benzoicacid;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(3-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone;(4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(4-(pent-4-yn-1-yloxy)phenyl)methanone;4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzoicacid; and4-((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzoicacid.
 13. The method of claim 11 wherein the compound of formula (I) isselected from:((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.14. The method of claim 11 wherein the compound of formula (I) isselected from:((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(4,4-difluorocyclohexyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.15. The method of claim 11 wherein the compound of formula (I) isselected from:((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-1-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyrimidin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;and((5R,6S)-5-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-(5-fluoropyridin-2-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol.16. The compound of claim 1 wherein:

is a fused 5- or 6-membered N-heteroaryl substituted by substitutedaryl, substituted aralkyl, substituted cycloalkyl or substitutedheteroaryl; R¹ is hydrogen; R² is —R⁶—OR⁷; R³ is —R⁶—OR⁷ or —R⁶—N(R⁸)₂;R^(4a) is alkyl and R^(4b) is hydrogen; R⁵ is alkyl or R⁵ is a directbond to the carbon at C14; each R⁶ is independently selected from adirect bond or a straight or branched alkylene chain; each R⁷ isindependently selected from hydrogen or alkyl; and each R⁸ isindependently selected from hydrogen or alkyl.
 17. The method of claim16 wherein the compound of formula (I) is selected from:(4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)(phenyl)methanone;(4-((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)(phenyl)methanone;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-(4-fluorophenoxy)phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanolhydrochloride;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-2-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-2-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyridin-4-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-1-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol;and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-5-methyl-2-(4-(pyrimidin-5-yloxy)phenyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol.18. The method of claim 16 wherein the compound of formula (I) isselected from:((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-2-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)methanol;and((5R,6S)-5-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1,7a-dimethyloctahydro-1H-inden-5-yl)-1-(4-methoxybenzyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)methanol.